Phase 1 Study of Lorlatinib (PF-06463922), an Oral Small Molecule Inhibitor of ALK/ROS1, for Patients With ALK-Driven Relapsed or Refractory Neuroblastoma
Phase: PHASE1
Conditions: Neuroblastoma
Sponsor: New Approaches to Neuroblastoma Therapy Consortium

 
NANT 2015-02:  PHASE 1 STUDY OF LORLATINIB (PF-06463922), AN ORAL SMALL MOLECULE 
INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY 
NEUROBLASTOMA 
 
NCT03107988 
 
Protocol Version 05.06.2022 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
1 
 
 
     
NEW APPROACHES TO NEUROBLASTOMA THERAPY (NANT) CONSORTIUM 
 
NANT 2015-02:  PHASE 1 STUDY OF LORLATINIB (PF-06463922), AN ORAL SMALL MOLECULE 
INHIBITOR OF ALK/ROS1, FOR PATIENTS  
WITH ALK-DRIVEN RELAPSED OR REFRACTORY NEUROBLASTOMA 
IND# __133273_______ 
 
COORDINATING CENTER 
Children’s Hospital Los Angeles / NANT Operations Center 
 
PARTICIPATING INSTITUTIONS AND CONTACT PHYSICIANS 
 
UCSF Benioff Children’s Hospital, 550 16th Street, 4th Floor Box 0434 San Francisco, CA 94158 
Kieuhoa Vo, MD, Phone: 415-476-3831; Email: kieuhoa.vo@ucsf.edu 
 
Children’s Hospital Los Angeles, 4650 Sunset Boulevard, MS 54 Los Angeles, CA 90027 
Araz Marachelian, MD, Phone: 323-361-8573; Email: amarachelian@chla.usc.edu 
 
Cincinnati Children’s Hospital, 3333 Burnett Avenue MLC 7015 Cincinnati, OH 45229 
Brian Weiss, MD, Phone: 513-636-9863; Email: brian.weiss@cchmc.org 
 
Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, CTRB 9006 Philadelphia, PA 19104 
Yael P. Mossé, MD, Phone: 215-590-0965; Email: mosse@chop.edu 
 
C.S. Mott Children’s Hospital, 1500 East Medical Center Drive, D4202 MPB Ann Arbor, MI 48109 
Rajen Mody, MD, Phone: 734-232-9335; Email: rmody@med.umich.edu 
 
Seattle Children’s Hospital, 4800 Sand Point Way Northeast, MS-6D1 Seattle, WA 98105 
Navin Pinto, MD, Phone: 206-987-5783; Email: navin.pinto@seattlechildrens.org 
 
Children’s Hospital Boston, Dana-Farber Cancer Institute, 450 Brookline Ave, Suite 350 Boston MA 02115 
Suzanne Shusterman, MD, Phone: 617-632-4901; Email: suzanne_shusterman@dfci.harvard.edu 
 
Hospital for Sick Children, 555 University Avenue, Toronto, Ontario Canada M5G1X8 
Daniel Morgenstern, MB BChir, Phone: 416-813-7654 Email: daniel.morgenstern@sickkids.ca 
 
Children’s Healthcare of Atlanta, 1760 Haygood Dr., HSRB E372, Atlanta, GA 30322 
Kelly Goldsmith, MD, Phone: 404- 727-2655; Email: kgoldsm@emory.org  
 
University of Chicago, Comer Children’s Hospital, 900 East 57th Street KCBD RM 5100 Chicago, IL 60637 
Ami Desai, MD, Phone: 773-843-3943; Email: adesai12@peds.bsd.uchicago.edu 
 
Cook Children’s Healthcare System, 901 Seventh Avenue, Suite 220 Fort Worth, TX 76104 
Meaghan Granger, MD, Phone: 682-885-4007; Email: mgranger@cookchildrens.org 
 
Children’s Hospital Colorado, 13123 East 16thAve. B-115, Aurora, CO 80045 
Margaret Macy, MD, Phone: 720-777-8856; Email: Margaret.macy@childrenscolorado.org 
 
Royal Marsden Hospital, 15 Cotswold Road, Sutton, Surrey, SM2 5PT, UK 
Lynley Marshall, MB BCh DCH MRCPCH PhD, Phone: +44 208 661 3678; Email: LynleyVanessa.Marshall@icr.ac.uk  
 
lnstitut Curie, 26 Rue d'Ulm, 75248 Paris Cedex 05, FRANCE 
Gudrun Schleiermacher, MD, Phone: +33 1 44 32 45 50; Email: gudrun.schleiermacher@curie.fr 
 
Protocol Chair 
Yael Mossé, MD 
Children’s Hospital of Philadelphia 
Phone:  215-590-0965 
Email: mosse@chop.edu  
Protocol Vice-Chair 
Kelly Goldsmith, MD 
Children’s Healthcare of Atlanta 
Phone: 404-727-2655 
Email: kgoldsm@emory.edu 
 
 
 
 
 
 
Activated: 09/05/2017 
             Version Date:  05-06-2022 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
2 
 
 
 
TABLE OF CONTENTS 
 
INFORMATION REGARDING CERTIFICATE OF CONFIDENTIALITY 
4 
IND SPONSOR 7 
ABSTRACT 
8 
1.0 GOALS AND OBJECTIVES 
16 
2.0 
BACKGROUND 
17 
2.1 
Neuroblastoma 
17 
2.2 
ALK as a tractable therapeutic target in Neuroblastoma 
17 
2.3 
Next generation TKI, lorlatinib (PF-06463922) in crizotinib-resistant ALK/ROS1+ 
preclinical models. 
19 
2.4 
Lorlatinib (PF-06463922) Adult Clinical Studies 
20 
2.5 
Adult Pharmacology / Pharmacokinetics / Correlative and Biological Studies 21 
2.6 
Lorlatinib Pediatric Clinical Studies 
26 
2.7 
Overview of Proposed Pediatric Study 
26 
2.8 
Weight gain and increased appetite expected with Lorlatinib 
46 
2.9 
Five Gene NB5 assay by TLDA for Neuroblastoma Tumor Cell Detection 
46 
3.0 
PATIENT ELIGIBILITY CRITERIA AND REGISTRATION 
52 
3.1 
Patient Preparation for Study Entry and Registration 
52 
3.2 
Inclusion Criteria 
53 
3.3 
Exclusion Criteria 
58 
3.4 
Regulatory 
58 
4.0 
TREATMENT PROGRAM 
59 
4.1 
Treatment Overview 
59 
4.2 
Dose Escalation Schedule 
60 
4.3  
Definition of Dose-Limiting Toxicity (DLT) 
62 
4.4       Treatment Duration and Criteria to Start Next Treatment Course 
70 
4.5 
Concomitant Therapy 
71 
5.0  
SUPPORTIVE CARE 
73 
5.1   
Prophylaxis for Pneumocystis Jiroveci Pneumonia (PJP) 
73 
5.2  
Use of Myeloid Growth Factors 
73 
5.3   
Antiemetic 
73 
6.0 
DRUG INFORMATION 
74 
6.1 
Lorlatinib (PF-06463922) 
74 
6.2 
Topotecan  (SKF-104864, Hycamtin®) 
76 
6.3 
Cyclophosphamide (Cytoxan) 
78 
6.4 Neulasta (PEG-FILGRASTIM) 
80 
6.5 
GRANULOCYTE COLONY STIMULATING FACTOR (G-CSF) 
81 
7.0    
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
83 
7.1 
Clinical and Laboratory Assessments 
83 
7.2 
Recommended Follow-Up Observations 
90 
7.3 
Documentation of Tumor Response 
91 
8.0 
PHARMACOKINETIC AND BIOLOGY STUDIES 
92 
8.1  
Lorlatinib Pharmacokinetics (PK) (Required) 
92 
8.2 
Correlative Pharmacodynamics Studies 
93 
8.3 
Correlative Biology Studies from Tumor Tissue and Bone Marrow (Optional) 94 
8.4 
Evaluation of Minimal Residual Disease by NB5 Assay 
95 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL AND OFF STUDY CRITERIA 
96 
9.1 
Criteria for Removal from Protocol Therapy 
96 
9.2 
Off Study Criteria 
96 
10.0 
STATISTICAL CONSIDERATIONS 
97 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
3 
 
 
10.1 
ENDPOINTS 
99 
10.2    STUDY DESIGN 
100 
10.3 
Statistical Analysis 
104 
10.4    Inclusion of Women and Minorities 
106 
11.0 
NANT RESPONSE CRITERIA V2.0 
107 
11.1 
Soft Tissue Response Criteria 
107 
11.2 
Bone Marrow Response Criteria 
109 
11.3. 
Bone Response Criteria using MIBG scans (for MIBG avid tumors) 
112 
11.4 
Bone Response Criteria using FDG-PET scans (only for MIBG non-avid tumors)
 
113 
11.5 
Urine Catecholamines 
114 
11.6 
Definition of Overall Response 
114 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
118 
12.1 
Purpose 
118 
12.2 
Definitions 
118 
12.3 
Expedited Serious Adverse Event Reporting to NANT Operations 
119 
12.4 
Expedited Adverse Event Reporting to the FDA 
119 
12.5 
NANT Operations Center Role in Expedited Adverse Event Reporting to the FDA 
and Participating Sites 
120 
12.6  
Adverse event reporting requirements for Pfizer Inc. 
121 
12.7 
Reporting Secondary AML/MDS 
121 
12.8   
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events
 
121 
13.0 
RECORDS AND REPORTING 
122 
14.0 
REFERENCES 
123 
APPENDIX I: 
PERFORMANCE STATUS SCALES/SCORES 
125 
APPENDIX II: BLOOD VOLUME SUMMARY FOR CORRELATIVE STUDIES 
126 
APPENDIX III: DOSING NOMOGRAMS 
127 
APPENDIX IV: NEUROPSYCHOLOGICAL ADMINISTRATION PROCEDURES BY AGE GROUP
 
133 
APPENDIX V: SAMPLE TEMPLATE OF NEUROPSYCHOLOGICAL STATUS REPORT 
136 
APPENDIX VI: DOSE ESCALATION AND EXPANSION COHORT (A1 & B1) SAMPLE CONSENT
 
137 
APPENDIX VII: LORLATINIB IN COMBINATION WITH CONVENTIONAL CHEMOTHERAPY 
(COHORT B2) SAMPLE CONSENT 
154 
APPENDIX VIII: DOSE EXPANSION COHORT A2: PATIENTS > 18 YEARS OF AGE SAMPLE 
CONSENT 
175 
APPENDIX IX:  SAMPLE ASSENT FORM COHORTS A1 AND B1 
190 
APPENDIX X:  SAMPLE ASSENT FORM COHORT A2 
193 
APPENDIX XI:  SAMPLE ASSENT FORM COHORT B2 
196 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
4 
 
 
INFORMATION REGARDING CERTIFICATE OF CONFIDENTIALITY 
 
The New Approaches to Neuroblastoma Therapy (NANT) consortium 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 family member, 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
5 
 
 
STUDY COMMITTEE 
 
STUDY CHAIR 
Yael P. Mossé, MD 
Children's Hospital of Philadelphia 
Division of Oncology 
3501 Civic Center Boulevard, CTRB 9006 
Philadelphia, PA 19104 
Office: 215-590-0965  
Fax: 267-426-0685 
Email: mosse@chop.edu 
STUDY STATISTICIAN 
Yueh-Yun Chi, PhD 
USC School of Medicine 
1355 San Pablo St. 
Los Angeles, CA 90033 
Email: ychi@chla.usc.edu  
STUDY VICE CHAIR 
Kelly Goldsmith, MD 
Children’s Healthcare of Atlanta 
1760 Haygood Drive, HSRB E372 
Atlanta, GA 30322 
Office: 404-727-2655 
Fax: 404-727-4455 
Email: kgoldsm@emory.edu 
COMMITTEE MEMBER 
Kimberly Kayser, PhD 
Vanderbilt University Medical Center  
Dept of Psychiatry and Behavioral Sciences  
1601 23rd Avenue South  
Room 3061D PHV 
Nashville, TN 37212-8645 
Phone : 615-936-0123 
Fax: 615-936-0130  
Email: kimberly.kayser@vumc.org 
COMMITTEE MEMBER 
Araz Marachelian, MD, MS 
Children’s Hospital Los Angeles, HemOncBMT 
4650 Sunset Boulevard, MS 54 
Los Angeles, CA 90027 
Office:323-361-8573 
Fax: 323-361-1803 
Email: amarachelian@chla.usc.edu 
 
COMMITTEE MEMBER 
Hiroyuki Shimada, MD, PhD 
Stanford University, School of Medicine 
300 Pasteur Dr., Room H1401 
Stanford, CA 94305 
Phone: 650-736-1783 
Email: HShimada@stanford.edu  
 
COMMITTEE MEMBER 
Julie Park, MD 
Seattle Children’s Hospital 
4800 Sand Point Way NE MS6D1 
Seattle, WA  98105 
Office: 206-987-1947 
Fax: 206-987-3946 
Email:julie.park@seattlechildrens.org 
COMMITTEE MEMBER 
Gerson Peltz, MD, MPH  
Pfizer Oncology 
445 Eastern Point Rd 
Groton, CT 06340  
Office: 857-488-5278 
Email: Gerson.Peltz@pfizer.com  
COMMITTEE MEMBER 
Katherine Matthay, MD 
UCSF School of Medicine, Mailstop 0434 
550 16th Street, 4th Floor 
San Francisco, CA 94158-2549 
Phone: 415-476-0603 
Fax: 415-476-5356 
Email: matthayK@peds.ucsf.edu 
COMMITTEE MEMBER 
Fariba Goodarzian, MD 
Children’s Hospital Los Angeles, Radiology 
4650 Sunset Boulevard, MS 81 
Los Angeles, CA 90027 
Office: 323-361-4162 
Fax: 323-361-8005 
Email: FGoodarzian@chla.usc.edu 
 
PROTOCOL COORDINATOR 
Suzy Ghazarian, MPA 
Children’s Hospital Los Angeles 
NANT Operations 
4650 Sunset Blvd, MS-54 
Los Angeles, CA  90027 
Phone: 323-361-5695 
Fax: 323-361-1803 
Email: sghazarian@chla.usc.edu 
COMMITTEE MEMBER  
Esther Berko, MD, PhD 
Children’s Hospital of Philadelphia  
Division of Oncology  
3501 Civic Center Boulevard, CTRB 3056 
Philadelphia, PA 19104 
Email: BERKOE@EMAIL.CHOP.EDU  
RESEARCH COORDINATOR 
NANT Operations Center 
Children’s Hospital Los Angeles 
4650 Sunset Blvd., MS-54 
Los Angeles, CA 90027 
Office:323-361-5687 
Fax:323-361-1803 
Email: nantcrf@chla.usc.edu 
NURSE CONSULTANT  
Beth Hasenauer, RN 
Children’s Hospital Los Angeles 
NANT Operations 
4650 Sunset Blvd, MS-54 
Los Angeles, CA  90027 
Phone: 323-361-5687 
Email: nantcrf@chla.usc.edu 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
6 
 
 
 
NANT CONSORTIUM INSTITUTIONS 
 
Kieuhoa Vo, MD 
UCSF Benioff Children’s Hospital 
550 16th Street, 4th Floor Box 0434 
San Francisco, CA 94158-2549 
Office: 415- 476-3831 
Fax: 415-476-5356 
Email: matthayk@peds.ucsf.edu 
Araz Marachelian, MD, MS 
Children’s Hospital Los Angeles 
Division of Hematology/Oncology 
4650 Sunset Boulevard, MS 54 
Los Angeles, CA 90027 
Office:323-361-8573 
Fax: 323-361-1803 
Email: amarachelian@chla.usc.edu 
 
Rajen Mody, MD 
C.S. Mott Children’s Hospital 
1500 E. Medical Center Drive D4202 MPB 
Ann Arbor, MI 48109-5718 
Office: 734-232-9335 
Fax: 734-615-0464 
Email: rmody@med.umich.edu 
Brian Weiss, MD 
Cincinnati Children’s Hospital 
Department of Pediatric Oncology 
3333 Burnett Avenue, MLC 7015 
Cincinnati, OH 45229 
Office:513-636-9863 
Fax: 513-636-3549 
Email: brian.weiss@cchmc.org 
Yael P. Mosse, MD 
Children's Hospital of Philadelphia 
Division of Oncology 
3501 Civic Center Boulevard, 
CTRB 9006 
Philadelphia, PA 19104 
Office: 215-590-0965  
Fax: 267-426-0685 
Email: mosse@chop.edu 
Suzanne Shusterman, MD 
Children’s Hospital Boston 
Dana-Farber Cancer Institute 
450 Brookline Avenue, Suite 350 
Boston, MA 02115 
Office: 617-632-4901 
Fax: 617-632-3270 
Email: 
suzanne_shusterman@dfci.harvard.edu 
Margaret Macy, MD 
Children’s Hospital Colorado 
13123 East 16thAve. B-115 
Aurora, CO 80045 
Office: 720-777-8856 
Fax: 720-777-7289 
Email: 
Margaret.macy@childrenscolorado.org 
Navin Pinto, MD 
Seattle Children’s Hospital 
Division Hematology/Oncology 
4800 Sand Point Way NE MS6D1 
Seattle, WA  98105 
Office: 206-987-5783 
Fax: 206-987-3946 
Email: 
navin.pinto@seattlechildrens.org 
Ami Desai, MD 
University of Chicago 
Comer Children’s Hospital 
900 East 57th Street KCBD, RM5100 
Chicago, IL 60637 
Office: 773-843-3943 
Fax:773-702-9881 
Email: adesai@peds.bsd.uchicago.edu  
 
Daniel Morgenstern, MB BChir 
Hematology-Oncology 
Hospital for Sick Children 
555 University Avenue, 
Toronto, Ontario Canada M5G1X8 
Phone: 416-813-7654 
Fax: 416-813-5327 
Email:daniel.morgenstern@sickkids.ca 
Kelly Goldsmith, MD 
Children’s Healthcare of Atlanta. 
1760 Haygood Dr., HSRB E372 
Atlanta, GA 30322 
Office: 404-727-2655 
Fax: 404-727-4455 
Email: kgoldsm@emory.edu 
Lynley Marshall, MB BCh DCH MRCPCH PhD 
Royal Marsden Hospital 
15 Cotswold Road, Sutton, Surrey, SM2 5PT. 
UK 
Office: +44 208 661 3678 
Email: LynleyVanessa.Marshall@icr.ac.uk  
Meaghan Granger, MD 
Cook Children’s Healthcare System 
901 Seventh Avenue, Suite 220 
Fort Worth, TX 76104 
Office: 682-885-4007 
Fax: 682-885-1713 
Email: mgranger@cookchildrens.org 
 
 
Gudrun Schleiermacher, MD, PhD 
lnstitut Curie 
26 Rue d'Ulm, 75248 Paris Cedex 05, 
FRANCE 
Office: +33 1 44  32 45 50 
Email: gudrun.schleiermacher@curie.fr 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
7 
 
 
IND SPONSOR 
 
Araz Marachelian, MD, MS 
Children’s Hospital Los Angeles 
Division of Hematology/Oncology  
4650 Sunset Boulevard, MS 54 
Los Angeles, CA 90027 
Office:323-361-8573 
Fax: 323-361-1803 
Email: amarachelian@chla.usc.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
8 
 
 
ABSTRACT 
 
Advances in treatments for children with high-risk neuroblastoma (NB) have, until recently, involved addition 
of cytotoxic therapy to dose-intensive regimens. In this era of targeted therapies, substantial efforts have 
been made to identify optimal targets for different types of cancer. The discovery of hereditary and somatic 
activating mutations in the oncogene ALK has now placed neuroblastoma among other cancers1-4, such as 
melanoma and non-small-cell lung cancer (NSCLC), which benefit from therapies with oncogene-specific 
small-molecule tyrosine kinase inhibitors. Crizotinib, the ATP-competitive ALK/Met/ROS1 inhibitor, has 
transformed the landscape for the treatment of NSCLC harboring ALK translocations and has demonstrated 
activity in preclinical models of ALK-driven neuroblastomas 5. These findings motivated a Phase 1 trial of 
crizotinib (PF-02341066) in children with refractory neuroblastoma or other malignancies driven by ALK 
rearrangements such as anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumors 
(IMTs) 6.  Results from this trial underscored the importance of ALK across histologically diverse tumors, 
but recorded less frequent responses in neuroblastoma than in ALK rearranged tumors – highlighting likely 
differences between therapeutic targeting of full-length ALK in neuroblastoma and of cytoplasmic ALK 
fusion proteins in ALCL, IMTs, and lung cancer.  Parallel preclinical work has further revealed differential 
sensitivity to crizotinib for the most common ALK variants observed in neuroblastoma 5,7,8, with F1174L and 
F1245C-mutated cells being resistant when compared with those expressing R1275Q-mutated ALK. 
Therefore, our goal has been to identify a next-generation ALK inhibitor with improved selectivity and 
potency to target these resistant mutants effectively.   
 
To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target 
intractable ALK variants such as F1174L.  We find that lorlatinib (PF-06463922) has high potency across 
ALK variants, and inhibits ALK more effectively than crizotinib in vitro.  Most importantly, lorlatinib induces 
complete tumor regression in both crizotinib-resistant and sensitive xenograft mouse models of NB, as well 
as in patient-derived xenografts (PDXs) harboring the crizotinib-resistant F1174L or F1245C mutations.  
These studies demonstrate that lorlatinib has the potential to overcome crizotinib resistance, and exerts 
unprecedented activity as a single agent against F1174L and F1245C ALK-mutated tumors, while also 
inducing durable responses in R1275Q xenografts.  Taken together, these results provide the rationale to 
move lorlatinib into clinical trials for treatment of patients with ALK-mutated NB. 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
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SIGNATURE PAGE 
NANT 2015-02: Phase 1 Study of Lorlatinib (PF-06463922), an Oral Small Molecule 
Inhibitor of ALK/ROS1, for Patients with ALK-Driven, Relapsed or Refractory 
Neuroblastoma Study Protocol Version 06/MAY/2022, Amendment 11A. 
 
This protocol has been approved by: 
 
Name: Araz Marachelian, M.D., M.S. 
Study Role: NANT Medical Director 
 
Signature: ________________________ 
Date:  ________________________ 
 
 
 
Name: Yael Mossé, M.D. 
Study Role: Study Chair 
 
Signature: ________________________ 
Date:  _________________________ 
 
 
 
This protocol describes the NANT 2015-02 ALK Study and provides information about 
procedures for patients taking part in the ALK Study. 
 
 
This protocol has been reviewed and acknowledged by:  
 
 
Name:   __________________________ 
Study Role: Site Principal Investigator 
 
Signature: ________________________ 
Date:  _________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
10 
 
 
EXPERIMENTAL DESIGN SCHEMA - with Amendment # 7, date 10-31-2019 
Lorlatinib will be given orally once daily continuously in 28-day courses. Lorlatinib will be provided as 5mg 
or 25mg tablets. PK studies will be performed during course 1 only and will be mandatory. 
 
Only patients with confirmed ALK fusion protein, ALK mutation or ALK amplification will enroll on this study. 
Cohort A1 and A2 will be initiated simultaneously and cohort assignment will be based on age and body 
surface area (BSA).  
 
Following activation of Amendment 7, cohort B2 will be initiated for patients ≤ 18 YOA at 95 mg/m2/dose 
which will be labeled “Dose Level 4B” in combination with chemotherapy. Once cohorts A1 and A2 are 
complete and the maximum tolerated dose (MTD) is identified and a recommended Phase II dose (RP2D) 
is selected, cohort B1 will be initiated for patients < 18 YOA, and cohort A2 will be expanded for adults >  
18 YOA at the RP2D, to provide single agent lorlatinib therapy for patients ineligible for cohort B2. Patients 
with prior exposure to ALK inhibitor therapy (except lorlatinib) are eligible to enroll on any cohort. See 
Section 4.0 for further cohort assignment details.  
 
Cohort Assignment Will Be As Follows:  
   
Schema for Dose Finding and Expansion Cohorts A1, A2 and B1 Lorlatinib (PF06463922)  
 
 
 
Cohort A1 (Dose escalation for patients < 18 YOA) 
Lorlatinib will be given orally once daily continuously for 28 days.  The dose level of lorlatinib will be assigned 
at the time of study registration.  The starting dose for cohort A1 is 45 mg/m2/dose (see Section 4.2 for dose 
escalation schedule) with dose escalation based on a 3+3 design with dose levels defined in Table 15a-d.  
 
Cohort A2 (Adult dose escalation & expansion)  
Adults > 18 years of age enrolled will follow a 3+3 dose escalation design with dose levels defined in Table 
15b.  Lorlatinib will be given orally once daily continuously for 28 days. Following the determination of the 
recommended phase 2 dose (RP2D), A2 will be expanded for patients ≥ 18 YOA who are ineligible for 
cohort B2.  
 
Cohort B1 (Limited Expansion) 
This limited expansion monotherapy cohort is open to patients ≥ 12 months of age and < 18 YOA who 
cannot enroll on Cohort B2 because (i) they are unable to tolerate topotecan and/or cyclophosphamide or 
(ii) if a B2 treatment slot is not available. B1 cohort will not begin enrollment until the recommended phase 
2 dose (RP2D) is established from the dose escalation cohort A1. Lorlatinib will be given orally once daily 
continuously for 28 days.  
 
Cohort B2: Combination with conventional chemotherapy (Dose escalation & expansion for patients 
< 18 YOA; expansion for patients > 18 YOA) 
Cohort B2 will initially open to patients ≥ 12 months of age and < 18 YOA. Lorlatinib will be given orally 
once daily continuously for 28 days starting at “dose level 4B” which is 95 mg/m2 (with maximum dose of 
150 mg) with Topotecan and Cyclophosphamide being given IV once daily on Days 1-5.  For patients < 18 
YOA, lorlatinib will follow a 3+3 dose escalation design with dose levels defined in Table 15c.  Once the 
RP2D in A2 is established, cohort B2 will open to patients > 18 YOA up to ≤ 30 YOA at the A2 RP2D in 
combination with Topotecan and Cyclophosphamide with no dose escalation. 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Cycle 1 
Day 28 
Disease evaluation 
Disease evaluations 
Cycle ≥2 
End of Cycles 
2, 4, 6, and then 
after every 4th 
cycle 
Lorlatinib PO once daily 
 
 
                Continue if no PD or DLT 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
11 
 
 
 
Schema for Cohort B2 Lorlatinib (PF06463922) In Combination with Conventional Chemotherapy  
 
Lorlatinib: PF-06463922 (QD) starting at 95 mg/m2 (see Table 15c). 
CPM: Cyclophosphamide 
TOPO: Topotecan 
MGF: Myeloid growth factor 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
12 
 
 
 
A. COHORT ASSIGNMENT OVERVIEW PRIOR TO AMENDMENT 4 
Cohort 
Cohort definition 
Age Range 
(in years) 
BSA for Cohort 
entry 
Prior ALK 
Inhibitor (ALKi) 
Status at 
Enrollment 
Enrollment 
Timing 
A1 
Dose Escalation 
≥ 12months & 
≤ 18 years 
Dose Level 1,  & 
2 
≤ 1.72m2 
N/A  
Study 
Initiation 
through 
dose 
escalation 
completion 
Dose Level 3 
≤ 1.42m2 
A2 
 
Adult & Large BSA 
Adult 
> 18 
years 
 
N/A 
N/A 
Adult: study 
initiation 
through 
study 
closure 
Large BSA 
≥12 
months 
& 
≤ 18 
years 
≥ 1.73m2 
while Dose Level  
1, & 2 are open 
Large BSA: 
≥ 1.43m2  
 only when 
A1 enrolling 
on DL 3 
≥ 1.43m2  
while Dose Level 
3 is open 
B1 
Expansion 
≥ 12 months & 
≤ 18 years 
N/A 
ALKi Naïve 
priority 
enrollment* 
Open when 
cohort A1 
closes & 
RP2D has 
been 
determined 
 
B2 
 
Combination with chemotherapy 
 
Prior ALKi 
exposure** 
*Prior ALKi exposure may enroll with SMC approval if patient cannot tolerate chemotherapy in B2 or if B2 is complete 
**ALKi naïve enrollment when B1 completed 
 
 

 
 
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B. COHORT ASSIGNMENT OVERVIEW AFTER ACTIVATION OF AMENDMENT 4 before Amendment 7  
Cohort 
Cohort 
Definition 
Age Range (in 
years) 
BSA for 
Cohort entry 
Prior ALK 
inhibitor 
(ALKi) Status 
at enrollment 
Enrollment 
Timing 
A1 
Dose 
Escalation 
≥ 12months & 
≤ 18 years 
Dose level 
4 & 5 
≤ 1.72m2 
N/A 
AMD 4 
through dose 
escalation 
completion 
A2 
Adult & Large 
BSA 
Adult 
> 18 
years 
N/A 
N/A 
AMD 4  
through study 
closure 
Large 
BSA 
≥12 
months 
& 
≤ 18 
years 
≥ 1.73m2 
While Dose 
level 4 & 5 are 
open 
B1 
Expansion 
≥ 12 months & 
≤ 18 years 
N/A 
ALKi Naïve 
priority 
enrollment* 
Open when 
cohort A1 
closes & RP2D 
has been 
determined 
 
B2 
 
Combination 
with 
chemotherapy 
Prior ALKi 
exposure** 
*Prior ALKi exposure may enroll with SMC approval if patient cannot tolerate chemotherapy in B2 or if B2 is complete     
**ALKi naïve enrollment when B1 completed 
  
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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C. COHORT ASSIGNMENT OVERVIEW AFTER ACTIVATION OF AMENDMENT 7  
 
Cohort 
Cohort Definition 
Age Range (in years) 
Enrollment Timing 
A1 
Dose Escalation 
≥ 12months & 
< 18 years 
Through dose escalation completion 
A2 
Adult & Large BSA 
Dose Escalation 
> 18 years 
Through dose escalation completion 
A2 
Adult Expansion 
> 18 years 
Open when A2 dose escalation cohort closes & RP2D 
determined for patients > 18 YOA not eligible for B2 
B1 
< 18 YO Expansion 
≥ 12 months & 
< 18 years 
Open when cohort A1 dose escalation closes & RP2D has 
been determined 
B2 
 
Combination with 
chemotherapy 
 
≥ 12months &  
< 18 years 
 
 
Dose level 4B enrolls concurrently with A1 and A2 dose 
escalation 
 
Dose level 5B enrolls if A1:DL5 and B2:DL4B are deemed 
tolerable  
> 18 years & ≤ 30 years 
Open after A2 dose escalation completion. Lorlatinib given at 
RP2D with no dose escalation 
B2 
Expansion 
≥ 12 months & 
≤ 30 years 
Open after RP2D for Cohort B2 for relevant age group is 
established 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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1.0 GOALS AND OBJECTIVES 
 
PRIMARY AIMS 
 
a. To determine a recommended phase 2 dose (RP2D) of lorlatinib administered orally to children, 
adolescents and adults with relapsed or refractory neuroblastoma who have tumor containing a 
confirmed pathogenic ALK fusion protein, ALK mutation or ALK amplification.   
b. To describe the toxicities of lorlatinib when administered to this population. 
c. To characterize the pharmacokinetics of single agent lorlatinib in children and adolescents with 
relapsed/refractory neuroblastoma. 
d. To define and describe the toxicities of lorlatinib in combination with topotecan and 
cyclophosphamide in children, adolescents and adults with relapsed or refractory neuroblastoma 
who have tumor containing a confirmed pathogenic ALK fusion protein, ALK mutation or ALK 
amplification administered on this schedule. 
e. To characterize the pharmacokinetics of lorlatinib when combined with topotecan and 
cyclophosphamide in children and adolescents with relapsed/refractory neuroblastoma  
 
SECONDARY AIMS 
 
a. To preliminarily evaluate the anti-tumor activity of lorlatinib within the confines of a Phase 1 
biomarker-driven study in children and adolescents with relapsed/refractory neuroblastoma 
harboring confirmed pathogenic ALK alterations. 
 
EXPLORATORY AIMS 
 
a. To describe the toxicities, pharmacokinetics, and anti-tumor activity of lorlatinib in the larger 
adolescent and adult population with relapsed or refractory neuroblastoma who have tumor 
harboring a confirmed pathogenic ALK fusion protein, ALK mutation or ALK amplification.   
b. To prospectively determine the overall frequency of circulating tumor cell-free DNA (ctDNA) 
detection and the profile of acquired somatic mutations in plasma from peripheral blood at study 
entry and at each anti-tumor evaluation time point. 
c. To describe the clonal heterogeneity and evolution of ALK and other genetic aberrations in relapsed 
neuroblastoma genomes by comparing matched tumor samples (diagnosis and recurrence) for 
detection of mutations, copy number alterations and translocations. 
d. To assess tumor burden with the NB5 assay [a 5-gene Taqman Low Density Array (TLDA)] prior 
and during treatment with lorlatinib.  
e. To describe the response of anti-tumor activity of lorlatinib in relation to prior exposure to ALK 
inhibition therapy. 
f. 
To evaluate cognitive and behavioral outcomes (refer to variables in Table 24) compared to 
baseline functioning in patients with relapsed/refractory neuroblastoma treated with lorlatinib.  
g. To characterize additional patterns of cognitive and behavioral functioning in child, adolescent, and 
adult populations with relapsed or refractory neuroblastoma to examine the association of relevant 
demographic and medical variables with change in performance overtime.  
                   

 
 
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2.0 
BACKGROUND 
 
2.1 
Neuroblastoma 
Neuroblastomas are embryonal tumors that arise from the sympathetic nervous system and 
represent the most frequently diagnosed malignancy in the first year of life.9 Approximately 50% of 
patients present with metastatic disease.  Many of these patients are either refractory to initial 
therapy or develop recurrent disease after receiving multimodal therapy.  The outcome for patients 
with recurrent or refractory disease remains poor. Novel approaches to treating these patients are 
required to improve their outcome.  MYCN amplification is present in approximately 25% of high-
risk neuroblastoma and portends a poor prognosis.10  More recently, Myc protein expression has 
been observed in neuroblastoma, appears to be independent of MYCN amplification, and also 
portends a poor prognosis.11 Current treatments rely on dose-intensive chemotherapy, radiation 
therapy, and immunotherapeutic targeting of the disialoganglioside GD2.12 The most recent clinical 
studies of high-risk neuroblastoma have focused on escalating dose intensity in both induction and 
consolidation therapies, with evidence that this improves outcome. The potential long-term adverse 
effects of increasing treatment intensity on survival of this childhood cancer are a major concern13, 
making it imperative that more effective and rational treatment strategies are developed. Future 
treatment strategies must rationally exploit known tumor-specific alterations. Kinases are critical 
components of cellular signal transduction cascades, and are key effectors of cell proliferation and 
differentiation. Our recent work provides the first evidence for oncogenic activation of ALK via 
mutation of the kinase domain, and these data provide the genetic basis for the observation of 
sensitization to ALK kinase inhibition. 
 
Current disease surveillance strategies for neuroblastoma patients rely on cross sectional imaging 
and MIBG scans along with urinary catecholamines as sensitive and specific signs of relapse, 
disease progression, or lack of treatment response. However, these methods are clearly insufficient 
to detect relapses or disease progression early enough to make a difference in clinical outcome for 
a significant subset of patients. Detecting circulating tumor DNA (ctDNA) in high-risk neuroblastoma 
patients may provide an additional sensitive method for disease surveillance. In prior pilot studies 
using older genomic techniques, children with neuroblastoma have been found to have high levels 
of ctDNA, especially at the time of diagnosis and relapse, and neuroblastoma specific genomic 
alterations have reliably been detected in the serum of these children including MYCN amplification 
and gain of chromosome 17q. We recently reported that 78% of relapsed high-risk neuroblastoma 
harbored lesions in the canonical RAS-MAPK growth promoting pathway, which is a major focus 
of recent targeted therapeutic development in many human cancers. Thus, prospective analysis of 
serial peripheral blood samples for ctDNA mutations at defined treatment time points has major 
diagnostic, monitoring and therapeutic decision-making implications for high-risk neuroblastoma 
patients. 
 
2.2 
ALK as a tractable therapeutic target in Neuroblastoma  
Several recent findings have positioned the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine 
kinase as the only tractable oncogene product for targeted therapy in neuroblastoma.  Germline 
and somatic aberrations in the gene encoding ALK are implicated in approximately 8% of all 
neuroblastomas3,4,14,15.  Within the high-risk subset of neuroblastoma patients, the overall 
frequency of ALK aberration at diagnosis is 14% (10% point mutations, 4% amplification) and 
correlates with inferior outcome 16.  We recently showed that relapsed NBs harbor an increased 
somatic mutational burden compared to primary tumors with enrichment of ALK-RAS-MAPK 
activating mutations nearly always present within subclonal populations at diagnosis17, and 
validated this in a recent retrospective review of the largest series of relapse samples studied to 
date18. Additional ALK mutations at relapse have also been reported19,20.  We posit that these 
mutations provide a selective advantage leading to chemoradiotherapy resistance. The activating 
mutations are found at several sites in the tyrosine kinase domain of full-length ALK 16, including 
three hot spots (R1275, F1174, and F1245).  These findings motivated a Phase 1 trial of the ATP-
competitive ALK/Met/ROS1 inhibitor crizotinib (PF-02341066) in children with refractory 
neuroblastoma or other malignancies driven by ALK rearrangements such as anaplastic large cell 
lymphoma (ALCL) and inflammatory myofibroblastic tumors (IMTs) 6.  Results from this trial 

 
 
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underscored the importance of ALK across histologically diverse tumors,but recorded less frequent 
responses in neuroblastoma than in ALK rearranged tumors – highlighting likely differences 
between therapeutic targeting of full-length ALK in neuroblastoma and of cytoplasmic ALK fusion 
proteins in ALCL, IMTs, and lung cancer.  Parallel preclinical work has further revealed differential 
sensitivity to crizotinib for the most common ALK variants observed in neuroblastoma5,7,21, with 
F1174L-mutated cells being resistant when compared with those expressing R1275Q-mutated 
ALK.  Despite real-time integration of these findings in the clinic, and a recommended phase 2 dose 
of crizotinib in pediatric patients that is nearly twice the adult maximum tolerated dose 6, these 
studies emphasize the need to identify an optimal inhibitor for direct ALK kinase inhibition in 
neuroblastoma in order to maximize clinical benefit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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2.3 
Next generation TKI, lorlatinib (PF-06463922) in crizotinib-resistant ALK/ROS1+ preclinical 
models.  
PF-06463922 (Pfizer) is an orally available potent and selective next generation Tyrosine-Kinase 
Inhibitor (TKI) of ALK and ROS1. In preclinical studies, lorlatinib demonstrated dose dependent 
inhibition of mutations conferring resistance to treatment with both first and second generation 
TKIs, including crizotinib22-24. Lorlatinib was discovered using structure-guided efforts to maintain 
potency across a range of resistance mutations and to optimize physicochemical properties25.  It 
is a potent macrocyclic ALK inhibitor with good absorption, distribution, metabolism, and 
excretion, as well as a low propensity for P-glycoprotein-mediated efflux and considerably 
improved central nervous system penetration.  Lorlatinib was also designed and optimized to 
penetrate the blood-brain barrier and has shown strong distribution in the central nervous system 
in preclinical studies25.  This is also likely to be a 
highly favorable attribute for use of lorlatinib in a 
disease like neuroblastoma that has a predilection for 
recurrence in this sanctuary site 26. 
 
In neuroblastoma cell line assays, lorlatinib inhibited 
ALK kinase activity (measured by inhibition of its 
autophosphorylation) with cell IC50’s of 1.5 nM and 
21 nM for EML4-ALK and EML4-ALK (L1196M), the 
most common mutation that occurs within the 
gatekeeper residue of the ALK kinase, which 
compares favorably to crizotinib IC50’s of 80 nM and 
841 nM, respectively) 27. Data from in vivo efficacy 
models bearing the EML4-ALK (L1169M] mutation 
predicted the efficacious concentration (Ceff) to be 
51 nM (unbound), which corresponds to achieving 
tumor stasis (100% tumor growth inhibition) in this 
preclinical model. We have demonstrated that 
lorlatinib overcomes crizotinib resistance of ALK 
variants in NB, and exerts unprecedented activity as 
a single agent against F1174L and F1245C ALK-
mutated tumors in preclinical models (Figure 1).  
Lorlatinib showed at least 3-4 fold higher potency 
than crizotinib in peptide phosphorylation assays, 
and its superior inhibition was consistently observed 
in cellular analysis of transforming ability.  In vivo, 
lorlatinib induced superior and complete tumor 
regression in cell-line and patient-derived xenograft 
mouse models harboring both crizotinib-sensitive and 
crizotinib-resistance 27 (Figure 1).  
At a tenfold lower dose (10mg/kg) than typically used 
for crizotinib (100mg/kg), lorlatinib induces complete 
tumor regression in both cell-line derived (Figure 1A 
and D) and patient-derived (Figure 1B and C) 
xenograft mouse models harboring the most common 
ALK mutations. Whereas crizotinib-treated mice in 
models harboring crizotinib-resistant ALK mutations 
(F1174L and F1245C) experienced rapid tumor 
growth on therapy, lorlatinib treated mice showed 
sustained complete responses for several weeks even 
after treatment was discontinued.  Additionally, in 
xenografts harboring the most common and relatively 
crizotinib-sensitive R1275Q ALK mutation, mice 
treated with lorlatinib have superior and sustained 
Figure 1. In vivo single-agent efficacy 
of PF-06463922 (red) compared with 
crizotinib (blue) in (A) SH-SY5Y 
neuroblastoma xenograft harboring an 
F1174L ALK mutation; (B) COG-N-453x 
Patient Derived Xenograft harboring an 
F1174L ALK mutation; (C) COG-N-426x 
Patient Derived Xenograft harboring an 
F1245C ALK mutation; and (D) NB-1643 
neuroblastoma xenograft harboring an 
R1275Q ALK mutation. 

 
 
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growth inhibition. We are now poised to rapidly develop this agent for integration with conventional 
chemotherapeutic agents in the treatment of patients with newly diagnosed ALK-driven 
neuroblastoma. 
 
2.3.1  
In Vitro Metabolism 
Lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways.  Oxidative 
metabolism of lorlatinib is primarily mediated by cytochrome CYP3A4 with minor contributions from 
CYP2C19, CYP2C8, and CYP3A5.  Glucuronidation of lorlatinib is mediated primarily by UGT1A4, 
with minor contribution from UGT1A3. 
 
2.4 
Lorlatinib (PF-06463922) Adult Clinical Studies 
 
2.4.1 
Adult Phase 1 Studies  
The phase 1 portion of a Phase 1/2 trial (NCT01970865) to assess the safety, pharmacokinetics 
and pharmacodynamics of single agent lorlatinib in adult patients with advanced ALK or ROS1 
translocated non-small cell lung cancer (NSCLC) was completed in July of 2015 and presented at 
the 2016 ASCO meeting.  Forty one patients with ALK+ NSCLC11 patients with ROS1+ NSCLC 
were enrolled across 7 QD dose levels and 3 BID dose levels. Forty four patients were evaluable 
for safety, 34 for overall tumor response, and 25 for intracranial response. One DLT occurred in 
the 200-mg QD cohort due to grade 1–2 cognitive effects. The objective response rate (95% 
confidence interval [CI]) was 44% (27–62), comprising 1 complete response, 10 confirmed partial 
responses, and 4 unconfirmed partial responses. In 25 patients evaluable for intracranial 
responses, of which 14 had CNS lesions as target lesions, the objective intracranial response rate 
(95% CI) was 36% (18–58), comprising 3 confirmed complete intracranial responses, 2 confirmed 
partial intracranial responses, 1 unconfirmed complete response and 2 unconfirmed partial 
intracranial responses. 50 (93%) experienced any treatment-related AE. Most treatment related 
AE’s were grade 1 or 2. Hypercholesterolemia/hypertriglycemia were controlled with statins and 
lipid lowering agents, if indicated.   While preclinical data showed pancreatic acinar atrophy in 14-
day ETS and 1-month regulatory toxicology studies in both rodent and non-rodent species, there 
was no clinical pancreatitis during phase 1, only grade 1-2 elevated lipase/amylase.  Peripheral 
neuropathy was usually mild and reversible upon dose hold. Mild to moderate CNS effects with a 
variety of presentations, including changes in speech, memory and mood, were observed in some 
patients receiving lorlatinib and were generally intermittent and managed with dose hold or 
reduction. There were 20 deaths, as of 5 May 2016; all were disease-related. 33.3% of patients 
had a treatment-related dose delay, 24.1% of patients had a treatment-related dose reduction and 
2 patients discontinued treatment due to treatment-emergent adverse events. None of the adverse 
events that resulted in treatment discontinuation were considered study drug related. The only DLT 
that occurred was at the 200 mg QD dose level, grade 2 CNS toxicity prevented the patient from 
getting recommended number of doses in the first course. Therefore, the RP2D was chosen to be 
100 mg QD, two dose levels below the DLT.  Table 1 below captures the treatment related Adverse 
Events observed in the adult phase 1/2 trial. 
 
 

 
 
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Table 1. Summary of Treatment Related, Treatment–Emergent Adverse Events by MedDRA Preferred 
Term Occurring in at Least 10% of Patients who Received 100 mg QD (Phase 1/2) 
Preferred Term 
Total (n=295) 
N 
(%) 
Any AEs 
281 
(95.3) 
**Hypercholesterolemia 
249  
84.4 
**Hypertriglyceridemia 
199 
67.5 
**Edema 
135  
45.8 
**Peripheral Neuropathy  
101  
34.2  
**Cognitive Effects  
70  
23.7 
Weight increased 
71  
24.1 
**Mood Effects  
46  
16.20  
**Fatigue 
50 
16.9 
Diarrhea 
37  
12.5 
Aspartate aminotransferase increased 
40  
13.6 
Alanine aminotransferase increased  
37  
12.5 
Arthralgia 
38 
12.9 
Lipase increased 
32 
10.8 
Constipation 
31 
10.5 
** refer to AE cluster terms OF COGNITIVE EFFECTS, EDEMA, FATIGUE, 
HYPERCHOLESTEROLEMIA, HYPERTRIGLYCERIDEMIA, MOOD EFFECTS, PERIPHERAL 
NEUROPATHY. List of Terms that comprise each cluster term as per MedDRA Version 24.0 can be 
found in Table 28 of the Investigator’s Brochure version dated OCT2021.  
 
2.4.2 
Adult Phase 2 Studies 
The phase 2 portion of the phase 1/2 trial of lorlatinib (NCT01970865) in patients with 
recurrent/refractory NSCLC was opened to accrual in September of 2015 and has completed 
enrollment (n = 295). The interim Clinical Study Report has been finalized. The RP2D of 100 mg 
was being studied for response rate in an estimated cohort of 240 patients. Cognitive and mood 
assessments were added to the patient evaluations to better characterize CNS events due to 
lorlatinib in this adult population.  
 
2.5 
Adult Pharmacology / Pharmacokinetics / Correlative and Biological Studies  
 
2.5.1 
Safety and Pharmacokinetics  
There are two ongoing clinical studies in patients with ALK-positive or ROS1-positive NSCLC.  
B7461001 is a single-agent study currently in phase 2 and described in detail below.  B7461006 is 
a phase 3 randomized controlled study evaluating lorlatinib versus crizotinib in treatment-naïve 
patients. 
 
The eight healthy volunteer studies that have been completed include two mass balance studies 
(B7461004 and B7461017), a relative biolavailability study (B7461005), an absolute bioavailability 
study (B7461007), a PPI study (B7461008), a DDI study with rifampin (B7461011), a DDI study 
with itraconazole (B7461012), and a bioequivalence study (B7461016).  
 
The studies with relevant safety and PK results are described in detail below.  
 
2.5.1.1 Safety and Pharmacokinetics from Study B7461001 
Study B7461001 is a phase 1/2, open-label, multicenter, multiple-dose, dose-escalation, safety, 
PK, pharmacodynamic (PD) and anticancer efficacy exploration study of lorlatinib as a single-agent 
in patients with advanced ALK+ and advanced ROS1+ NSCLC. 
 
B7461001 is being conducted in 2 parts: Phase 1 (lorlatinib as acetic acid solvate) and Phase 2 
(lorlatinib as free base). The phase 1 portion of the study was aimed at estimating the MTD for 
single-agent lorlatinib in dose-escalation cohorts in patients with advanced ALK+ or advanced 

 
 
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ROS1+ NSCLC with or without asymptomatic CNS metastases, and enrolled 54 patients. The 
phase 2 portion of the study has completed enrollment (n = 295) and is being conducted with single-
agent lorlatinib at the identified MTD/RP2D in patients with advanced ALK+ NSCLC and patients 
with advanced ROS1+ NSCLC, with or without asymptomatic CNS metastases. 
 
The phase 1 portion of this study employed a modified continual reassessment method (CRM) to 
estimate the MTD. The CRM was initiated at 25 mg QD and recommended escalation to 75, 100, 
150, and 200 mg QD based on no DLTs observed at the previous dose levels tested. At 200 mg 
QD, one (1) DLT occurred in a patient who failed to receive 16 of the planned 21 lorlatinib doses in 
Course 1 due to Grade 1 vision change, abnormal dreams and photosensitivity reaction, and Grade 
2 aphasia and cognitive disorder.  Although the CRM model recommended continuation to the next 
higher dose above 200 mg QD, a decision was made among the treating investigators and the 
sponsor to re-test lower doses (ie, outside of the CRM model) to better understand and evaluate 
the CNS effects observed at the higher dose levels.  These CNS effects observed consisted of 
mostly Grade 1 and Grade 2 transient effects including changes in speech, cognition, memory and 
mood.  
 
Overall, 100 mg QD was a well-tolerated dose. None of the patients at this dose required dose 
reduction and dose delays were not attributed to CNS effects, but rather to hypercholesterolemia 
or hypertriglyceridemia or disease related events.  Based on the PK data observed, simulated 
patient exposure showed the 100 mg QD dose to be the lowest dose exceeding the lorlatinib Ceff 
of 150 ng/mL during the majority of the dosing course once steady-state was reached.  The Ceff of 
150 ng/mL was a concentration predicted to result in >80% tumor growth inhibition of the ALKG1202R 
resistance mutation. 
 
The 100 mg QD dose was chosen as the recommended phase 2 dose (RP2D) based on the entirety 
of the safety, efficacy, and clinical pharmacology data.  The RP2D was not based on formal DLT 
and MTD determinations due to the nature of the cognitive effects.  
 
As of June 2020, lorlatinib has been administered to a total of 295 patients at the 100 mg QD dose. 
HYPERCHOLESTEROLEMIA was reported in 84.4% of patients,  HYPERTRIGLYCERIDEMIA 
was reported in 67.5% of patients, EDEMA was reported in 45.8% of patients, PERIPHERAL 
NEUROPATHY was reported in 34.2% of patients, weight increased was reported in 24.1% of 
patient, and COGNITIVE EFFECTS were reported in 23.7% of patients. The most frequent > Grade 
3 treatment emergent adverse events in the 100 mg QD group were HYPERTRIGLYCERIDEMIA 
(19.4%), and HYPERCHOLESTEROLEMIA (18.0%).   
 
The phase 2 portion of the study has completed enrollment (n = 295). Overall the safety profile has 
been consistent with that observed in the phase 1.  A notable finding about PR prolongation is 
described at the end of the clinical summary. 
 
In the Phase 1 portion of this study, patients received lorlatinib doses ranging from 10-200 mg QD 
and 35-100 mg BID. Single- and multiple-dose PK data were available in a total of 43 patients 
respectively. Of these patients, 39 and 37 patients had adequate single- and multiple-dose PK for 
AUC estimation respectively. Pharmacokinetic parameters are summarized in Table 6.1-1 and 6.1-
2 of the IB, after single and multiple QD dose administration. 
 
After single oral administration of lorlatinib tablets (as acetic acid solvate) under fasted conditions, 
median time to peak plasma concentrations (Tmax) were between 1 and 2 hours across the 
evaluated dose levels. Following attainment of peak plasma concentration (Cmax), lorlatinib plasma 
concentrations showed a bi-exponential decline with a terminal elimination half-life of 19.0-28.8 
hours, apparent oral clearance (CL/F) of 6.7-11.5 L/hr and volume of distribution (Vz/F) of 233-382 
liters across the evaluated dose levels. Variability in PK was observed with a coefficient of variation 
(CV %) of 28-77% for AUCinf and 19-45% for Cmax following single oral administration. 
 
 

 
 
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After repeated QD oral administration, steady state should have been achieved before Day 15 
based on the lorlatinib single dose terminal elimination half-life. The accumulation indices defined 
as the ratios of the lorlatinib AUC over the dosing interval (τ) of 24 hours at steady state (AUCτ) to 
the AUC over a post-dose period of 24 hours after single dose administration (AUC24) across the 
dose range tested, were less than the predicted values based on the calculated lorlatinib elimination 
rate (kel) and τ (Table 6.1-1 of the IB), suggesting auto-induction may play a role in lorlatinib 
disposition. 
 
PK data (January 2016) after 100 mg single and multiple dosing in Phase 1 with lorlatinib tablets 
(as acetic acid  solvate) are summarized in Table 2. The AUC over a post-dose period of 24 hours 
after single dose administration (AUC24) across the dose range tested was less than the predicted 
values. 
 
PR interval prolongation has been observed in both healthy volunteer studies (Study B7461008) 
and clinical trials (Study B7461001). In the healthy volunteer Study B7461008, the PR interval 
prolongation was associated with 1 episode of transient second- degree atrioventricular (AV) block 
(Mobitz type 1; Wenckebach). In the clinical Study B7461001, the PR interval prolongation may 
have been associated with the progression of pre-existing AV block to complete heart block. When 
the complete heart block was identified, the patient was immediately evaluated and subsequently 
treated by placement of an implanted pacemaker. In response to the observation of PR interval 
prolongation, data from all available human studies (approximately 100 patients in clinical studies 
and 45 in single dose healthy volunteer studies) were reviewed. Additional instances were identified 
of asymptomatic increases in the PR interval, usually most notable during Cmax (1-2 hours post-
dose). Of note, the patients with a PR interval > 200 msec were generally those with a baseline 
value at the upper end of the normal range. The ECG changes appear limited to the PR interval, 
with no impact on QRS or QT intervals. This impact on the PR interval is supported by preclinical 
animal studies, as described in the current IB. 
 
Weight increase with lorlatinib has been reported preclinically in rats treated with lorlatinib, with 
females being more affected than males. Weight gain has been reported in the adult Phase 1/2 
trial, Study B7461001. Of 295 patients treated at 100 mg QD, Grade 1-2 weight gain was observed 
in 56 (19.0%) patients and Grade 3 weight gain was observed in 15 (5.1%) patients28. In the adult 
studies, B7461001 and B7461006, weight gain was not a reason for permanent treatment 
discontinuation, and temporary treatment discontinuation and dose reduction rates were low (0.8% 
and 1.1%, respectively). Based on these findings, weight gain is not a dose-limiting toxicity. 

 
 
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Table 2. B7461001 Summary of Lorlatinib Single and Multiple Doses PK Parameters Following 100 
mg QD Administration 
 
Dose 
N, na 
AUCb 
(ng•hr/mL) 
Cmax 
(ng/mL) 
Tmax 
(hr) 
t1/2 
(hr) 
CL/F 
(L/hr) 
Vz/F 
(L) 
Phase 1 
Single Dose 
16, 16 8672 (28) 577 (44) 
2.0 (1.0-4.0) 
22.2 (26) 
11.5 (28) 
357 (38) 
Multiple 
16, 14 5065 (32) 569 (32) 
1.0 (1.0-4.0) 
NA 
20.0 (32) 
NA 
 
Phase 2 
Single Dose 
19, 17 9529 (40) 696 (40) 
1.0 (0.5-4.0) 
23.2 (40) 
10.5 (40) 
329 (43) 
Multiple 
26, 15 5078 (32) 581 (31) 
1.0 (0.5-3.0) 
NA 
19.7 (32) 
NA 
Source data: artifact ID 11523892, 11523893, 11515888 and 11515887 
Geometric mean (geometric %CV) for AUC, Cmax, CL/F, and Vz/F; arithmetic mean (%CV) for t1/2; median (range) for Tmax 
The Japanese patients were also included in this analysis 
aN=number of patients whose PK data were available, n=number of patients with adequate data for PK parameter estimation 
bAUCinf reported for single-dose and AUCτ for multiple dosing 
 
In vitro data indicated that lorlatinib is associated with time-dependent inhibition of CYP3A.  The 
CYP3A substrate drug midazolam was given alone and 14 days after administration of 25 mg QD 
and 150 mg QD of lorlatinib to a total of 6 patients.  Preliminarily, both AUCinf and Cmax geometric 
mean (CV%) of midazolam were reduced by about 48 and 63% and 24 and 18% in the presence 
of daily lorlatinib at 25 mg and 150 mg QD doses respectively, presumably due to lorlatinib 
induction of CYP3A.  Concomitant use of lorlatinib with medications which are CYP3A substrates 
has potential to reduce the concentration of sensitive CYP3A substrates.  
 
2.5.1.2 Safety and Pharmacokinetics from Study B7461004 
Study B7461004 is a completed Phase 1 study which evaluated the mass-balance and 
pharmacokinetics of lorlatinib in 6 healthy male subjects after a single oral 100 mg dose of 
radiolabeled lorlatinib containing approximately 100 µCi of [14C] PF-06463922. 
 
Preliminary results indicate a mean of 47.73% of the radioactivity was recovered in urine and 
40.91% was recovered in feces through the last collection interval.  Most of the administered 
radioactivity was recovered in the first 144 hours post dose (85.11%).  The overall mean recovery 
of radioactivity in urine and feces samples was 88.64% over the 288-hour study, with recovery in 
individual subjects ranging from 83.6 to 90.8%. 
 
Preliminary information indicates the presence of metabolites in circulating plasma, urine and feces. 
In the current B7461012 study, samples will be collected to describe the PK of the identified 
metabolite(s).   
 
2.5.1.3 Safety and Pharmacokinetics from B7461005 
Study B7461005 is a completed Phase 1/2, randomized open-label study in 19 healthy volunteers 
to estimate the relative bioavailability of two new lorlatinib formulations (free base and maleate salt) 
(Test) compared to the formulation of the lorlatinib acetic acid (Reference). The results supported 
the switch to a tablet formulation of lorlatinib as the free base in all future clinical trials.  
 
2.5.1.4 Safety and Pharmacokinetics from Study B7461008 
Study B7461008 is a completed Phase 1 study in 24 healthy volunteers, designed to evaluate the 
effect of rabeprazole and food on the pharmacokinetics of lorlatinib and to assess the relative 
bioavailability of an oral solution of lorlatinib to the tablet formulation of lorlatinib. The results of this 
study indicated that a high fat meal had no effect on the systemic exposure of lorlatinib. 
Furthermore, the proton pump inhibitor rabeprazole had only a marginal effect on the systemic 
exposure of lorlatinib. Hence, the current recommendation is that lorlatinib can be given orally 
regardless of food, proton pump inhibitors, H2-receptor antagonists, and locally acting antacids. 
 

 
 
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Preliminary safety data from this study recently identified asymptomatic PR prolongation. In one 
healthy volunteer, the PR interval prolongation was associated with one episode of transient 
second degree atrioventricular (AV) block (Mobitz type 1; Wenkebach).  Subsequently, 
retrospective review of patients in the clinical study B7461001, found one patient with the PR 
interval prolongation that may have been associated with the progression of pre-existing AV block 
to complete heart block.  When the complete heart block was identified, the patient was immediately 
evaluated and subsequently treated by placement of an implanted pacemaker.  
 
In response to the observation of PR interval prolongation, data from all available human studies 
(approximately 100 patients in clinical study B7461001 and 45 in single dose healthy volunteer 
studies) were reviewed.  Additional instances were identified of asymptomatic increases in the PR 
interval (> 200 msec), usually most notable at the time of Cmax (1-2 hours post-dose) in healthy 
volunteers.  Of note, the subjects with a PR interval > 200 msec were generally those with a 
baseline values at the upper end of the normal range. 
 
The ECG changes appear limited to the PR interval, with no impact on QRS or QT intervals. This 
impact on the PR interval is supported by preclinical animal studies, as described in the current 
Investigator Brochure. Although isolated PR interval prolongation (first or second degree AV block) 
may not pose an immediate risk to patient safety, the potential for development of complete heart 
block warrants that future studies exclude patients with a baseline PR interval ≥ 220 msec, or 2nd 
or 3rd degree AV block (unless an implanted pacemaker is in place).  Further, for healthy volunteers 
in this study the upper limit of normal for PR interval will be defined as PR interval of 180 msec. 
 
Additional information for this compound may be found in the single reference safety document 
(SRSD), which for this study is the Investigator’s Brochure.   
 
2.5.1.5 Safety and Pharmacokinetics from Study B7461011 
Study B7461011 was a phase 1 open-label, two-period, two-treatment, fixed-sequence crossover 
study to estimate the effect of multiple dose rifampin on a single dose of lorlatinib in 12 healthy 
volunteers.  
 
Co-administration of multiple doses of rifampin (600 mg QD) decreased lorlatinib (100-mg single 
dose) total exposure (AUCinf) by 85% and decreased the peak exposure (Cmax) by 76% relative 
to a single lorlatinib 100 mg dose given alone. Co-administration with multiple doses of rifampin in 
this study also led to reversible, severe increase of LFT values (AST and ALT) in healthy volunteers; 
there were no concurrent increases in total bilirubin.  
 
Overall, the use of strong inducers of CYP3A4/5 with lorlatinib is contraindicated. 
 
2.5.1.6. Safety and Pharmacokinetics from B7461012 
Study B7461012 was a Phase 1, open-label, 2-period, fixed-sequence, crossover study to 
investigate the effect of the strong CYP3A inhibitor, itraconazole, on lorlatinib PK in healthy 
subjects.  A total of 16 subjects were screened, assigned to treatment, and completed the study.   
Each enrolled subject received lorlatinib 50 mg, 75 mg or 100 mg alone in Period 1 and then 
lorlatinib 50 mg, 75 mg, or 100 mg in combination with multiple dose itraconazole in Period 2 after 
a washout period of at least 10 days between lorlatinib doses in Periods 1 and 2.  Following 
administration of lorlatinib in each period, subjects underwent serial PK sampling.   
Following the coadministration of lorlatinib and itraconazole, lorlatinib AUCinf and Cmax values for 
all subjects were higher compared to when lorlatinib was administered alone.  For the lorlatinib 100 
mg cohort, the geometric mean lorlatinib AUCinf and Cmax values following co-administration of 
itraconazole increased by 42% and 24%, respectively, compared to when lorlatinib was 
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Lorlatinib was well tolerated in this study.  No deaths, SAEs, severe AEs, permanent 
discontinuations, or temporary discontinuations due to AEs were reported. 
2.6 
Lorlatinib Pediatric Clinical Studies 
There have been no other pediatric studies to date of lorlatinib. 
 
2.7 
Overview of Proposed Pediatric Study 
This will be a phase 1 dose-finding study of lorlatinib to determine the maximum dose that is safe 
and tolerable in children with relapsed/refractory neuroblastoma. This will also be a biomarker 
driven protocol, whereby only patients whose tumor harbor a known activating ALK alteration 
(mutation, amplification, fusion) will be eligible for treatment with single agent next-generation ALK 
inhibitor, lorlatinib, and with lorlatinib in combination with conventional chemotherapy.  The anti-
tumor activity of this drug both alone and in combination with chemotherapy will be assessed in a 
preliminary fashion within the confines of this phase 1 trial, both during the dose escalation and 
during the expansion phase and combination phase, with lorlatinib given at the recommended 
phase 2 dose. Dose escalation will use the standard 3+3 rules, with 3 doses planned prior to 
Amendment 4. Two more dose levels were added post Amendment 4. Please see Table 15a-d for 
dose escalation schema for Cohort A1, Cohort A2 and Cohort B2. All treatment cohorts including 
the dose expansion cohort will allow for enrollment of ALK+ patients previously treated with other 
ALK inhibitors (crizotinib and ceritinib have both been studied in pediatric patients). Additionally, 
patients with evidence of disease in the CNS will be eligible for this study so long as eligibility 
criteria are met. Approximately 60-75 patients are expected to be enrolled in the study overall. 
 
Rationale for combining Lorlatinib with Topotecan and Cyclophosphamide. We have shown 
that crizotinib, when combined with conventional chemotherapy agents, restores sensitivity in 
preclinical models harboring both sensitive and de novo resistant ALK mutations 27, and this has 
served as the rationale for integration of crizotinib with standard of care chemotherapy in the 
recently activated Children’s Oncology Group Phase 3 trial (ANBL1531) with tumor ALK 
mutations/fusions/amplification. However, we are cognizant that there is limited rationale for this 
approach, especially in the maintenance phase of therapy when children with resistant ALK 
mutations will be exposed to single agent crizotinib  5,7,8 . The objective of this trial is to define the 
recommended phase 2 dose and anti-tumor activity of lorlatinib as a single agent across the range 
of NB-specific ALK mutations, and to define the toxicity profile and optimal dose of lorlatinib in 
combination with chemotherapy. This will provide data of this combination for future consideration 
of lorlatinib in upfront neuroblastoma trials. 
 
Based on the review of the agents and their toxicities, there are no predicted overlapping toxicities 
of the combination. 
 
Pfizer Pharmacologists have reviewed the published literature from the UW Drug Interaction 
Database (DIDB) (Copyright University of Washington, accessed on 9/25/2019) on topotecan and 
cyclophosphamide (topo/cy) metabolism and drug interaction potential.  There are no predicted 
drug-drug interactions (DDIs) with topo/cy that could alter lorlatinib exposure. Based on lorlatinib 
clinical DDI studies, at steady state, lorlatinib induces CYP3A and P-gp to moderate extent and 
CYP2B6 and CYP2C9 and UGT to a weak extent via PXR activation. Thus, it is reasonable to 
assume that lorlatinib may have similar effects on other PXR related enzymes and transporters 
such as CYP2C19 and BCRP. Topotecan is a substrate of BCRP and P-gp. Cyclophosphamide is 
a substrate of CYP2B6, CYP2C19, and CYP2C9. Thus, lorlatinib will likely mildly/moderately 
reduce the exposure of topotecan while mildly increasing the exposure of the active metabolite of 
cyclopphosphamide. Given there will be a mild difference in exposure, there is no reason to expect 
increase risk of toxicity with concomitant use of lorlatinib, and topotecan or cyclophosphomide due 
to PK interaction. 
 
To assess biological correlates of efficacy, we will access banked tumor DNA and/or tissue blocks 
from diagnosis and relapse (when available), as well as bone marrow prior to and while on 
treatment from participating patients. We will also obtain peripheral blood at study entry and at each 

 
 
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disease surveillance time point to determine the overall frequency of ctDNA detection of ALK 
alterations as a potential marker of minimal residual disease, and the profile of acquired somatic 
mutations during therapy. It has been known for decades that human solid tumors, as well as their 
nucleic acids, are present in the circulation of patients, but only recently has technological advances 
made it possible to consider clinical application of methodologies to detect circulating tumor DNA 
(ctDNA) in patients.29,30 For children with high-risk neuroblastoma, we envision these so-called 
“liquid biopsies” as providing not only an improved method for more precise disease surveillance, 
but by coupling detection with Next Generation Sequencing (NGS) technology, we also can 
noninvasively and comprehensively quantify clonally acquired oncogenic mutations that may be 
leveraged with targeted molecular therapies. Although somatic mutations in newly diagnosed 
neuroblastomas are present in only 10-15% of high-risk patients,31-35 recent data suggests that 
neuroblastomas frequently acquire new alterations in known oncogenic pathways under the 
selective pressures of cytotoxic chemotherapy.19,20,36 The study will include mandatory 
pharmacokinetic studies. 
 
2.7.1  
Preliminary Toxicity Update of NANT 2015-02 Study (as of October 2019)  
Hematological toxicities have been mild on this study thus far, the most frequently seen are the 
following: Anemia was seen in 11/29 (37%) patients, 3 of which were grade 3+.  
 
The following are the most common non-hematological toxicities observed which were at least 
possibly related to lorlatinib. Metabolic category: Weight gain was noted in 25/29 (86%) patients, 8 
of which were grade 3. Increased appetite (grade 1) was noted in 13/29 (44%) patients. 
Hypertriglyceridemia was noted in 25/29 (86%) patients, 3 of which were grade 3+.  Hyperglycemia 
was noted in 7/29 (24%) patients, 2 of which were grade 3+. Glucose intolerance was noted in 2/29 
patients (7%) patients (Grade 2 = 1, Grade 3 = 1). Cholesterol high was noted in 24/29 (83%) 
patients (Grade 2 = 9, Grade 3 = 2).  
 
Neuropsychological Category: Cognitive disturbance (grade 1) was noted in 4/29 (13%) patients. 
Concentration impairment (grade 1) was noted in 6/29 (20%) patients. Memory impairment was 
noted in 7/29 (24%) patients (Grade 1 = 6, Grade 2 = 1). Agitation (grade 1 = 2, grade 4 = 1) was 
noted in 3/29 patients. Anxiety was noted in 5/29 (17%) patients (Grade 1 = 4, Grade 2 = 1).  
Depression (grade 1) was noted in 2 /29 patients. Psychosis, suicidal ideation, and suicidal attempt 
(grade 4) was noted in 1/29 patients. Peripheral sensory neuropathy was noted in 3/29 (10%) 
patients (Grade 1 = 2, Grade 2 = 1). Fatigue (grade 1) was noted in 6/29 (20%) patients. Nausea 
(grade 1) was noted in 8/29 (27%). 
 
2.7.2 
Preliminary PK Data for NANT 2015-02 Study (as of August 2019) 
Twenty-nine patients in total enrolled to date on the NANT Phase 1 trial have had adequate 
pharmacokinetic sampling completed after the first course of Lorlatinib and the results analyzed.  
 
The preliminary PK data used in this analysis was based on nominal collection times and quality 
controlled, non-quality assured bio-analytical data. The PK parameters were determined by non-
compartmental analysis (Pharsight; Phoenix WinNonlin version 7.0).  
 
 
Table 4-9 and associated plots (Figure 2-13), the lorlatinib plasma pharmacokinetic (PK) 
parameters and concentration-time profiles for dose level 1 (45 mg/m2), dose level 2 (60 mg/m2), 
dose level 3 (75 mg/m2), dose level 4 (95 mg/m2), dose level 3A (100 mg), and dose level 4A (150 
mg) are presented, respectively. 
 
Note: Some half-life estimates could not be reliably estimated and hence the PK parameters should 
be interpreted with caution. 
 
Overall, the plasma PK patterns of lorlatinib in pediatric patients with ALK-positive neuroblastoma 
are similar to the PK patterns of lorlatinib in adult patients with advanced ALK-positive or advanced 
ROS1-positive non-small cell lung cancer. As demonstrated by both the concentration-time profiles 

 
 
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and the PK parameter summaries, the lorlatinib plasma exposure after multiple dosing (Cycle 1 
Day 15) is reduced as compared to after single dose (Cycle 1 Day 1); the lack of expected 
accumulation with multiple dosing indicates auto-induction, which is also seen in adult patients.  
 
The lorlatinib steady state plasma exposure observed at dose level 3 in pediatric patients is 
generally in the range of exposures observed in adults at the 100 mg QD dose level, which is the 
current approved dose in adult NSCLC patients. At dose level 3 the lorlatinib steady state AUCtau 
and Cmax was  4155 ng•hr/mL and 645.5 ng/mL, respectively, as compared to the adult 100 mg QD 
steady-state AUCtau and Cmax of 5650 ng•hr/mL and 576.5 ng/mL, respectively (B7461001 Clinical 
Study Report, Table 38. Descriptive Summary of Plasma Lorlatinib PK Parameters Following 100 
mg QD Dosing of Lorlatinib in Phase 2).  
 
The lorlatinib steady-state plasma exposure observed at dose level 4 in pediatric patients is 
generally in the range of exposures observed in adults at the 200 mg QD dose level, which is the 
maximum tested dose in adult NSCLC patients. At dose level 4 the lorlatinib steady-state AUCtau 
and Cmax was 7545 ng•hr/mL and 1003 ng/mL, respectively, as compared to the adult 200 mg QD 
steady-state AUCtau and Cmax of 8690 ng•hr/mL and 1095 ng/mL (n=2, arithmetic mean values 
reported), respectively (B7461001 Clinical Study Report, Table 23. Summary of Plasma Lorlatinib 
Pharmacokinetic Parameters Following Multiple Oral Doses).  
 
The preliminary PK data used in this analysis was based on nominal collection times and quality 
controlled, non-quality assured bio-analytical data. The PK parameters were determined by non-
compartmental analysis (Pharsight; Phoenix WinNonlin version 7.0).  
 
 
Table 4. Lorlatinib Plasma PK Parameter Summary Statistics by Visit for Dose Level 1 (45 mg/m2) 
Parameters, Units 
Parameter Summary Statistics by Visit for Dose Level 1 (45 
mg/m2) 
Single dose (Cycle 1 Day 1) 
Multiple dose (Cycle 1 Day 15) 
Number of Subjects 
3 
3 
AUCinf [ng•hr/mL]a 
4093 (64) 
NE 
AUCtau [ng•hr/mL] 
3526 (60) 
2473 (64) 
CL/F [L/hr]a 
9.298 (49) 
15.39 (31) 
Cmax [ng/mL] 
404.7 (65) 
354.5 (55) 
Tmax[hr] 
1.00 (1.00-2.00) 
1.00 (1.00-2.00) 
Vz/F [L] 
101.7 (70) 
NE 
t½ [hr]a 
7.935 ± 2.999 
NE 
Geometric mean (geometric %CV) for all summarized parameters except:  median (range) for Tmax; 
arithmetic  mean ± Std Dev for t½, 
AUCinf= Area under the plasma concentration-time profile from time zero extrapolated to infinite time; 
AUCtau= Area under the concentration-time profile from time zero to time tau (24 hours); CL/F= Apparent 
oral clearance; Cmax= Maximum observed plasma concentration; Tmax= Time for Cmax; Vz/F= Apparent 
volume of distribution; NE= not estimable. 
aNote: some half-life estimates could not be reliably estimated and hence the PK parameters should be 
interpreted with caution.  
 
 
 
 

 
 
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Figure 2. Dose Level 1 (45 mg/m2) Lorlatinib Plasma Concentration-Time Profiles by Patient for 
Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
 
A. 
 
 
 
 
 
 
B. 
 
For the semi-log plot, if the concentration was 0, it was substituted as lower limit of quantification 
(LLOQ(/2 or 1.25 ng/mL 
 

 
 
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Figure 3. Dose Level 1 (45 mg/m2) Lorlatinib Median Plasma Concentration-Time Profiles by Visit 
(Cycle 1 Day 1 and Cycle 1 Day 15) (A: Linear; B: Semi-Log) 
 
A. 
 
 
 
 
 
 
 
 
 
B. 
 
 
 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL.  
 
 
 
 
 
 
 

 
 
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Table 5. Lorlatinib Plasma PK Parameter Summary Statistics by Visit for Dose Level 2 (60 mg/m2) 
Parameters, Units 
Parameter Summary Statistics by Visit for Dose Level 2 (60 
mg/m2) 
Single dose (Cycle 1 Day 1) 
Multiple dose (Cycle 1 Day 15) 
Number of Subjects 
3 
3 
AUCinf [ng•hr/mL]a 
6720 (43) 
NE 
AUCtau [ng•hr/mL] 
6020 (38) 
3927 (10) 
CL/F [L/hr]a 
7.544 (26) 
12.91 (23) 
Cmax [ng/mL] 
907.3 (36) 
492.2 (33) 
Tmax[hr] 
1.00 (1.00-1.00) 
2.00 (1.00-2.00) 
Vz/F [L] 
71.55 (46) 
NE 
t½ [hr]a 
6.810 ± 2.305 
NE 
Geometric mean (geometric %CV) for all summarized parameters except:  median (range) for Tmax; 
arithmetic  mean ± Std Dev for t½, 
AUCinf= Area under the plasma concentration-time profile from time zero extrapolated to infinite time; 
AUCtau= Area under the concentration-time profile from time zero to time tau (24 hours); CL/F= Apparent 
oral clearance; Cmax= Maximum observed plasma concentration; Tmax= Time for Cmax; Vz/F= Apparent 
volume of distribution; NE= not estimable. 
aNote: some half-life estimates could not be reliably estimated and hence the PK parameters should be 
interpreted with caution.  
 

 
 
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Figure 4. Dose Level 2 (60 mg/m2) Lorlatinib Plasma Concentration-Time Profiles by Patient for 
Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
 
A. 
 
 
 
 
 
 
B. 
 
 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL 

 
 
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Figure 5. Dose Level 2 (60 mg/m2) Lorlatinib Median Plasma Concentration-Time Profiles by Visit 
for Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
A. 
 
 
 
 
 
 
 
B. 
 
 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL.  
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table 6. Lorlatinib Plasma PK Parameter Summary Statistics by Visit for Dose Level 3 (75 mg/m2) 
Parameters, Units 
Parameter Summary Statistics by Visit for Dose Level 3 (75 
mg/m2) 
Single dose (Cycle 1 Day 1) 
 
Multiple dose (Cycle 1 Day 15) 
 
Number of Subjects 
3 
3 
AUCinf [ng•hr/mL]a 
5997 (33) 
NE 
AUCtau [ng•hr/mL] 
5580 (32) 
4155 (46) 
CL/F [L/hr]a 
10.77 (12) 
15.54 (26) 
Cmax [ng/mL] 
704.5 (38) 
645.4 (5) 
Tmax[hr] 
1.00 (1.00-2.00) 
2.00 (1.00-6.00) 
Vz/F [L] 
92.09 (13) 
NE 
t½ [hr]a 
5.937 ± 0.418 
NE 
Geometric mean (geometric %CV) for all summarized parameters except:  median (range) for Tmax; 
arithmetic mean ± Std Dev for t½, 
AUCinf= Area under the plasma concentration-time profile from time zero extrapolated to infinite time; 
AUCtau= Area under the concentration-time profile from time zero to time tau (24 hours); CL/F= 
Apparent oral clearance; Cmax= Maximum observed plasma concentration; Tmax= Time for Cmax; Vz/F= 
Apparent volume of distribution; NE= not estimable. 
aNote: some half-life estimates could not be reliably estimated and hence the PK parameters should be 
interpreted with caution.  
 
 

 
 
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Figure 6. Dose Level 3 (75 mg/m2) Lorlatinib Plasma Concentration-Time Profiles by Patient for 
Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
 
A. 
 
 
 
 
       
B. 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL 
 
 
 

 
 
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Figure 7. Dose Level 3 (75 mg/m2) Lorlatinib Median Plasma Concentration-Time Profiles by Visit 
for Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
A. 
 
 
 
 
 
 
 
B. 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL. 
 
 
 
 
 

 
 
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Table 7. Lorlatinib Plasma PK Parameter Summary Statistics by Visit for Dose Level 4 (95 mg/m2) 
Parameters, Units 
Parameter Summary Statistics by Visit for Dose Level 4 (95 
mg/m2) 
Single dose (Cycle 1 Day 1) 
 
Multiple dose (Cycle 1 Day 15) 
 
Number of Subjects 
9b 
8 
AUCinf [ng•hr/mL]a 
10960 (49) 
NE 
AUCtau [ng•hr/mL] 
9970 (43) 
7545 (53) 
CL/F [L/hr]a 
6.493 (46) 
9.800 (31) 
Cmax [ng/mL] 
1148 (58) 
1003 (42) 
Tmax[hr] 
2.00 (1.00-24.00) 
1.00 (1.00-4.00) 
Vz/F [L] 
57.43 (55) 
NE 
t½ [hr]a 
6.255 ± 1.412 
NE 
Geometric mean (geometric %CV) for all summarized parameters except:  median (range) for Tmax; 
arithmetic mean ± Std Dev for t½, 
AUCinf= Area under the plasma concentration-time profile from time zero extrapolated to infinite time; 
AUCtau= Area under the concentration-time profile from time zero to time tau (24 hours); CL/F= Apparent 
oral clearance; Cmax= Maximum observed plasma concentration; Tmax= Time for Cmax; Vz/F= Apparent 
volume of distribution; NE= not estimable. 
aNote: some half-life estimates could not be reliably estimated and hence the PK parameters should be 
interpreted with caution.  
bThe parameters AUCinf, CL/F, Vz/F, and t½ have 8 subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Figure 8. Dose Level 4 (95 mg/m2) Lorlatinib Plasma Concentration-Time Profiles by Patient for 
Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
A. 
 
 
 
 
 
 
 
B. 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL. 
 
 

 
 
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Figure 9. Dose Level 4 (95 mg/m2) Lorlatinib Median Plasma Concentration-Time Profiles by Visit 
for Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
A. 
 
 
 
 
 
 
 
B. 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL. 
 
 

 
 
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Table 8. Lorlatinib Plasma PK Parameter Summary Statistics by Visit for Dose Level 3A (100 mg) 
Parameters, Units 
Parameter Summary Statistics by Visit for Dose Level 3A (100 
mg) 
Single dose (Cycle 1 Day 1) 
 
Multiple dose (Cycle 1 Day 15) 
 
Number of Subjects 
5b 
5 
AUCinf [ng•hr/mL]a 
10070 (61) 
NE 
AUCtau [ng•hr/mL] 
7636 (58) 
6846 (75) 
CL/F [L/hr]a 
9.935 (61) 
14.61 (75) 
Cmax [ng/mL] 
603.7 (95) 
788.9 (86) 
Tmax[hr] 
1.00 (1.00-2.00) 
2.00 (1.00-4.00) 
Vz/F [L] 
128.4 (72) 
NE 
t½ [hr]a 
9.140 ± 2.197 
NE 
Geometric mean (geometric %CV) for all summarized parameters except:  median (range) for Tmax; 
arithmetic mean ± Std Dev for t½, 
AUCinf= Area under the plasma concentration-time profile from time zero extrapolated to infinite time; 
AUCtau= Area under the concentration-time profile from time zero to time tau (24 hours); CL/F= Apparent 
oral clearance; Cmax= Maximum observed plasma concentration; Tmax= Time for Cmax; Vz/F= Apparent 
volume of distribution; NE= not estimable. 
aNote: some half-life estimates could not be reliably estimated and hence the PK parameters should be 
interpreted with caution.  
bThe parameters AUCinf, CL/F, Vz/F, and t½ have 4 subjects 
 
 

 
 
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Figure 10. Dose Level 3A (100 mg) Lorlatinib Plasma Concentration-Time Profiles by Patient for 
Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
A. 
 
 
 
 
 
 
 
B. 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL. 
 
 
 

 
 
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Figure 11. Dose Level 3A (100 mg) Lorlatinib Median Plasma Concentration-Time Profiles by Visit 
for Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
A. 
 
 
 
 
 
 
 
B. 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL. 
 
 

 
 
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Table 9. Lorlatinib Plasma PK Parameter Summary Statistics by Visit for Dose Level 4A (150 mg) 
Parameters, Units 
Parameter Summary Statistics by Visit for Dose Level 4A (150 
mg) 
Single dose (Cycle 1 Day 1) 
 
Multiple dose (Cycle 1 Day 15) 
 
Number of Subjects 
4 
4 
AUCinf [ng•hr/mL]a 
11410 (6) 
NE 
AUCtau [ng•hr/mL] 
9606 (10) 
6143 (18) 
CL/F [L/hr]a 
13.14 (6) 
24.42 (18) 
Cmax [ng/mL] 
836.7 (17) 
638.3 (17) 
Tmax[hr] 
2.00 (1.00-2.00) 
2.00 (1.00-4.00) 
Vz/F [L] 
163.7 (19) 
NE 
t½ [hr]a 
8.707 ± 1.315 
NE 
Geometric mean (geometric %CV) for all summarized parameters except:  median (range) for Tmax; 
arithmetic mean ± Std Dev for t½, 
AUCinf= Area under the plasma concentration-time profile from time zero extrapolated to infinite time; 
AUCtau= Area under the concentration-time profile from time zero to time tau (24 hours); CL/F= Apparent 
oral clearance; Cmax= Maximum observed plasma concentration; Tmax= Time for Cmax; Vz/F= Apparent 
volume of distribution; NE= not estimable. 
aNote: some half-life estimates could not be reliably estimated and hence the PK parameters should be 
interpreted with caution.  
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
44 
 
 
Figure 12. Dose Level 4A (150 mg) Lorlatinib Median Plasma Concentration-Time Profiles by Visit 
for Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
A. 
 
 
 
 
 
 
 
B. 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL. 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
45 
 
 
Figure 13. Dose Level 4A (150 mg) Lorlatinib Median Plasma Concentration-Time Profiles by Visit 
for Cycle 1 Day 1 and Cycle 1 Day 15 (A: Linear; B: Semi-Log) 
A. 
 
 
 
 
 
 
 
B. 
 
For the semi-log plot, if the concentration was 0, it was substituted as LLOQ/2 or 1.25 ng/mL. 
 
 
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
46 
 
 
2.8 
Weight gain and increased appetite expected with Lorlatinib  
Non-Clinical Data: 
Increase of body weight and food consumption was observed following administration of lorlatinib 
to rats. The magnitude of change was significantly greater in females than males. Inhibition of TrkB 
is identified as the likely biologic rationale-these kinases are involved in appetite regulation and 
metabolic balance. 
 
Clinical Data: 
Adult studies: Weight increase with lorlatinib has been reported in the adult Phase 1 and Phase 2 
study. Of 262 evaluable patients in the phase 2, 80 (30.5%) patients increased by 10–20% of their 
baseline weight and 33 (12.6%) patients gained >20% of their baseline weight. The adult studies 
have reported this based on weight as a data point, and not as a reported adverse event. Weight 
gain appears to be more prominent in females and other phase 1 studies of TrkB inhibitors have 
reported weight gain, consistent with the underlying biological rationale for this effect. In the adult 
studies of lorlatinib, weight gain has not been a reason for dose delay or reduction.  
 
As of November 09, 2017 at the time of amendment 2a, 3 patients had enrolled on Cohort A1 Dose 
level 1 (45mg/m2).  All 3 patients experienced weight gain with therapy.  Two patients experienced 
grade 2 weight gain, and 1 experienced grade 3 weight gain.  There were no associated toxicities 
with the weight gain, specifically no patients experienced dose limiting toxicities of increased 
glucose, cholesterol or triglycerides.  These patients had increased appetite that resulted in weight 
gain.  The study committee reviewed the known preclinical and adult data and based on that 
analysis, grade 3 weight gain was excluded as a dose limiting toxicity.   
 
As of November 7, 2018, at the time of interim Dose Level 4 evaluation, eighteen patients were 
evaluable for weight gain.  Weight gain was observed in 16/18 patients. Of which 4/18 had grade 
3 weight gain, 9/18 had grade 2 weight gain, and 3/18 had grade 1 weight gain. In addition, 
associated with the weight gain, the BMI of enrolled patients was also increased with two patients 
reaching the ≥95% BMI according to age and sex. However, hyperglycemia has not been a 
common finding in this pediatric study with only one adult patient with a baseline severe obesity 
developing type 2 difficult to control diabetes. The study management committee agreed there is a 
potential for metabolic syndrome with this agent. The committee recommended the addition of 
hemoglobin A1c (HbA1c) measurement at time of fasting lipid panels and glucose measurements.  
 
As of January 21, 2020, after enrollment of the third patient on DL 5 and the sixth patient on DL 4A, 
32 patients were evaluable for weight gain. Weight gain was observed in 28/32 patients of which 
8/32 had grade 3 weight gain, 14/32 had grade 2 weight gain, and 6/32 had grade 1 weight gain.  
 
2.9 
Five Gene NB5 assay by TLDA for Neuroblastoma Tumor Cell Detection 
Dr. Robert Seeger’s laboratory developed the NB5 assay, a five gene TLDA array for sensitive 
detection of neuroblastoma tumor cells in peripheral blood and bone marrow. Five genes 
[chromogranin A (CHGA), doublecortin (DCX), dopadecarboxylase (DDC), paired-like homeobox 
2B (PHOX2B), and tyrosine hydroxylase (TH)] are highly expressed by neuroblastoma cell lines 
and tumors. These same genes are rarely expressed by normal blood cells, peripheral blood stem 
cells (PBSC), and bone marrow. Four housekeeping genes are used for quality control and data 
analysis. Heterogeneity in expression of the detection genes among neuroblastoma cell lines 
(n=22) and primary untreated stage 4 neuroblastoma tumors (n=23) is minimal. However, the use 
of five genes assures that heterogeneity will not impact tumor cell detection.  
 
Spiking experiments demonstrate the sensitivity of neuroblastoma cell detection using this 5-gene 
signature. Detection sensitivity with five genes (including TH) is superior to that of a single gene 
(TH). The five-gene detector has nearly 100% sensitivity to detect neuroblastoma RNA at a dose 
of 10-5, whereas the TH-only detector has sensitivity of <60%. In terms of neuroblastoma cell 
detection, the 5-gene signature can detect a 10-6 neuroblastoma cell frequency in PBMC with 81% 
probability compared to <30% for a TH-alone detector.  
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
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TLDA Detection Gene Score (DG score) is highly correlated with Immunocytology Score (number 
of tumor cells/106 total cells) when Immunocytology is positive in bone marrow. Forty-four 
unselected fresh bone marrow specimens were tested by both assays. The rank correlation 
between the TLDA DG Score and Immunocytology Score was r = -.93 (p < 0.001), which 
demonstrates a clear relationship between the two assays. The TLDA assay also can detect tumor 
cells in bone marrow that are not detected by Immunocytology. Thirty-six of the 44 bone marrows 
were negative by Immunocytology, but 20 of these were positive by TLDA. These data further 
confirm that the TLDA assay is more sensitive than Immunocytology for detecting tumor cells. 
Moreover, detection of occult bone marrow tumor cells by TLDA appears to have clinical relevance. 
In patients with newly diagnosed high-risk neuroblastoma, detection of tumor cells by TLDA in a 
bone marrow sample negative by Immunocytology at the end of therapy was associated with 
significantly worse event-free survival than bone marrow samples negative for tumor cells by TLDA 
assay.  
 
The current study includes an exploratory aim to evaluate neuroblastoma cell detection in blood 
and bone marrow by TLDA. These samples will be obtained as part of the companion NANT biology 
study (NANT 2004-05).   
 
2.10 
Adult Cohort with Lorlatinib Monotherapy (Cohort A2)  
 
Five evaluable patients enrolled on Cohort A2 Dose Level 3A with lorlatinib monotherapy at 
100mg/day. This dose level was reviewed by the Collaborative Governance Committee (CGC) and 
the decision was made to escalate to Dose Level 4A with lorlatinib monotherapy at 150mg/day. An 
amendment was required to revise the study design to add the Cohort A2 Dose level 4A at 
150mg/day. With Amendment 4, the activation of Dose Level 4A was initiated on 18JUN2018. Six 
patients were enrolled on Dose Level 4A. Patient toxicity and PK data were reviewed by the CGC 
and determined this to be the RP2D. The decision was made to expand Dose Level 4A to an 
additional 6 patients for further analysis of toxicity and PK data. Four additional evaluable patients 
enrolled on the expansion Dose level 4A. The CGC reviewed and compared Dose level 3A (5 total 
patients) with the Dose level 4A (10 total patients) patient toxicity and PK data on two separate 
meetings; 15SEP2021 and 30NOV2021. Preliminary PK data  showed comparable exposure at the 
100mg/day and 150mg/day dose levels. There were additional toxicities seen with the patients 
enrolled on the 150mg/day dose level. Therefore, the CGC decided to further expand Dose level 
3A (100mg/day) to 5 more patients for a total of 10 evaluable patients on this dose level for a better 
comparison of toxicity/response data as well as PK. This data will then allow for final determination 
for recommended phase 2 dose (RP2D) of this patient population. Cohort B2 (lorlatinib in 
combination with chemotherapy) for the adult patient population will also enroll at 100mg/day.  
 
2.11  
Rationale for Protocol Amendments  
 
Amendment #1 v 6-7-2017 
Pre-activation amendment dealt with updates and clarifications in eligibility, required observations, 
toxicity monitoring, dose modifications and statistical design, Corresponding informed consent 
template changes were made, in addition to administrative changes. 
 
Amendment #2A v 12-15-2017 
In addition to editorial, administrative changes and updates to participating institutions, this 
amendment covers important updates to the eligibility section, drug information changes, 
clarifications to the required observations section and changes to the informed consent template.   
Of note: 1) Requirement for a specific biopsy proven MIBG non-avid site to be present at the time 
enrollment was removed; 2) Time required from last biologic neoplastic agent was decreased from 
14 to 7 days; 3) Grade 3 weight gain was added as an exclusion to non-hematological dose limiting 
toxicities; 4) Restrictions to the administration of CYP3A inhibitors while on protocol therapy was 
removed due to updated knowledge on lorlatinib metabolism from the updated version of the IB; 5) 
Frequency of CBC checks were decreased due to lack of hematological toxicities. 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
48 
 
 
Amendment #3 v 3-7-2018 
There was one serious, unexpected event in a patient who began treatment on NANT 2015-02 
Cohort A2 (100mg QD). The patient is a 27 year old male who experienced grade 3 hyperglycemia, 
grade 3 hypertriglyceridemia, grade 2 hypertension, grade 1 cholesterol, grade 1 weight gain, and 
grade 1 peripheral neuropathies on Course 3 Day 26. Patient has no personal history of diabetes, 
but has a BMI of 40 and  a strong family history of diabetes. Grade 3 hyperglycemia persists despite 
interruption of lorlatinib and initiation of therapy for Type 2 diabetes. 
 
Upon review of prior experience with lorlatinib, of the 295 adult patients who received lorlatinib 
(100mg QD) on Ph1/2 trials, grade 3 treatment-related AE of hyperglycemia was reported to be 
0.7%.  
 
Review of NANT 2015-02 thus far all patients have experienced weight gain, grades 1-3 without 
associated hyperglycemia.  
 
Although patient was obese (BMI 40) and had a strong family history of diabetes, considering age 
and weight gain during therapy and acute onset of hyperglycemia (grade 3), the study team 
considers grade 3 hyperglycemia and hypertriglyceridemia probably related to lorlatinib therapy. 
However, exact potential risk of this specific toxicity in others is unknown. 
 
The risk of hyperglycemia was therefore added to the consent document as part of Amendment 3 
due to the information based on this event. 
 
Amendment #4 v 6-7-2018  
Evaluation of neuroblastoma patients on the highest dose level (DL3, 75 mg/m2) demonstrated no 
DLTs or cognitive deficits, supporting safety and tolerability of lorlatinib in pediatric population as 
of April 2018. PK data also demonstrates that acceptable levels of lorlatinib are achieved in children 
comparable to adults. Further evaluation of compelling preclinical data in neuroblastoma, however, 
reveal that lorlatinib doses required for antitumor potency in neuroblastoma are actually higher than 
effective lorlatinib doses in preclinical NSCLC models, with mouse to human equivalent dosing 
suggesting that Dose level 3 may be insufficient to target ALK driven neuroblastoma. This is likely 
due to the different patient population being tested and the different biology of ALK driven 
neuroblastoma compared to NSCLC. 
 
The study committee discussed the available toxicity, response and PK data and in order to 
maximize lorlatinib exposure for an anti-neuroblastoma response proposed to amend the study to 
include two additional dose escalations at Dose Level 4: 95 mg/m2, Dose Level 5: 115 mg/m2 (27% 
and 53% increases from Dose level 3), and to add dose levels  150 mg (similar  to dose level 4) 
and 200mg (similar  to dose level 5) to the adult cohort A2, and to adopt a 3+3 dose escalation 
design in Cohort A2 independent of that in Cohort A1. 
 
While neurocognitive effects are a concern at higher doses as previously seen in one adult at the 
200 mg flat dosing who experienced a DLT. Overall the adult experience shows that the CNS 
effects are mild to moderate with a variety of presentations, including changes in speech, memory 
and mood, and were generally intermittent and managed with dose hold or reduction. These effects 
are reversible upon cessation of the drug and/or dose reduction and are being closely monitored 
within this protocol and these symptoms will be captured in real time in subsequent cycles.  
 
For safety purposes, for patients enrolled after activation of Amendment 4, no more than two 
patients can simultaneously be enrolled on Course 1 of therapy in each of Cohorts A1 and A2. 
Furthermore, due to concern about possible delayed neurocognitive toxicities, the DLT evaluation 
period has been extended to include both Course 1 and Course 2, with any DLT during Course 1 
but only neurocognitive DLTs during Course 2 counting for dose escalation/de-escalation 
decisions.   
 

 
 
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49 
 
 
Two additional neuropsychological exploratory aims were added as part of Amendment 4 in order 
to adequately describe the results of the neuropsychological testing in this trial. 
 
This amendment also includes the change in the NANT 2015-02 Study Statistician from Susan 
Groshen, PhD to Richard Sposto, PhD.   
 
Footer #6 in required observations table 23 was updated to allow for course extension due to  
scheduling conflicts.  
 
Amendment #5 v 12-18-2018 
This protocol amendment is being implemented in order to add newly identified risks from the 
Investigator’s Brochure (v 10/2018) of pneumonitis, caution with use of machines/driving and 
decreased effectiveness of hormonal contraception. In addition, due to weight gain observed on 
NANT 2015-02 trial, closer evaluation of potential metabolic syndrome was instituted with fasting 
lipid and glucose measurements and hemoglobin A1c measurements. 
 
Amendment #6 v 04-30-2019 
This protocol amendment is being implemented in order to update the risks of lorlatinib based on 
the most recent toxicity data available from the B7461001 adult trial.  Other minor revisions made 
to this amendment are outlined in the cover memo and tracked changes version of the amendment.  
 
Amendment #7 v 10-31-2019 
Evaluation of neuroblastoma patients enrolled on Cohort A1 on the highest dose level (DL4, 95 
mg/m2) demonstrated no DLTs in courses 1 and 2 in five evaluable patients, supporting safety and 
tolerability of DL4 of lorlatinib in patients < 18 YOA. Therefore, Cohort A1 dose escalated to Dose 
Level 5 (115 mg/m2/day) on 9/18/2019.   
 
Evaluation of neuroblastoma patients enrolled on Cohort A2 showed that 1/5 adult patients on the 
highest dose level (DL4A, 150 mg daily) had a DLT of Grade 4 psychosis in course 2 of therapy 
that improved upon dose hold. Upon retreatment, patient had recurrent grade 4 psychosis.  Cohort 
A2 which was already expanded is pending evaluation  of an additional adult patient at DL4A to 
confirm tolerability and safety. No further dose escalation is planned for patients > 18 YOA on A2. 
Based on the severity of the neuropsychological toxicity, additional safeguards were added with 
restrictions of acute and chronic severe neuropsychological disorders in eligibility,  and not allowing 
retreatment for grade 4 CNS effects. Neuropsychological Assessment Schedule and Reporting 
Section 7.1.2.3 was also updated to include language for monitoring of psychosis. Psychosis was 
also added as a rare (<5%) risk of lorlatinib in the protocol and consent documents.  
 
Given the safety and tolerability of DL4 as a single agent in patients ≤ 18 YOA, the Study Committee 
determined DL4 to be the starting dose to use in combination with chemotherapy in Cohort B2 for 
patients ≤ 18 YOA. As such this amendment is being implemented to open Cohort B2 using 95 
mg/m2 (150 mg maximum) daily of lorlatinib in combination with topotecan and cyclophosphamide 
(Cohort B2 dose level 4B) in patients ≤ 18 YOA. Cohort B2 will activate and enroll concurrently with 
ongoing dose escalation cohorts A1 and A2.   For patients ≤ 18 YOA: If dose level 5 in cohort A1 
and dose level 4B on cohort B2 are tolerated, cohort B2 will escalate to dose level 5B of lorlatinib 
in combination with chemotherapy. For patients > 18 YOA: Once the RP2D is determined on cohort 
A2, then B2 will also open to patients > 18 to ≤ 30 YOA at the RP2D with no dose escalation. 
Patients > 18 will remain on the A2 expansion cohort with single agent lorlatinib at the RP2D. 
 
In addition, a few additional changes to cohort B2 were included. 
• 
Given the target age population to treat with lorlatinib chemotherapy combination are newly 
diagnosed HR NBL patients, the eligibile age for cohort B2 has been changed to ≤ 30 YOA.    
• 
With amendment 4, the DLT evaluation period for neurocognitive toxicities for cohort A1 was 
extended to to 2 courses. Since combination with chemotherapy is not likely to increased this 
specific toxicity and since single agent data is already available for this toxicity, the DLT period 
for cohort B2 will be limited to course 1.    

 
 
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50 
 
 
• 
After completion of 4 courses of combination therapy, an option to continue with single agent 
lorlatinib for this patient cohort will also be available. 
 
Following activation of Amendment 7, patients with prior ALK inhibitor exposure may enroll on any 
open cohort of the study.  
 
Adults >18 YOA who are not eligible for B2 may continue to enroll in single agent lorlatinib cohort 
A2 that will be expanded at the RP2D once it is determined.  
 
Due to rare grade 3 hyperglycemia in two patients on this current study, the study committee has 
reviewed how to best manage high glucose in this study.  With amendment 7,  Grade 3 
hyperglycemia will no longer be considered a DLT but Grade 3 glucose intolerance will continue to 
be a DLT as per CTCAE V4.0.  This was instituted because the study committee believes that 
assessing the level of glucose intolerance by symptoms and need for medical management is a 
better indication of persistent hyperglycemia adverse events compared to isolated blood sugar 
levels that could be transient and be medically less meaningful.  
 
In addition, supportive care management guidelines for elevated HbA1C, Grade 2 fasting 
hyperglycemia, peripheral neuropathy and peripheral edema have also been added since these 
toxicities have been observed during dose escalation. Lastly, the table for statin drug choice for 
hypercholesterolemia has been updated.  
 
The optional correlative study for ctDNA has been revised to collect 2 tubes (8.5ml/tube) instead of 
1 tube per time point due to better DNA extraction yield.  
 
Additionally, the consents were revised to reflect the changes made in Amendment 7. 
 
Amendment #8 v. 03-23-2020 
 
This protocol amendment clarified language in dose modifications in regards to grade 4 neutropenia 
and thrombocytopenia for Cohort B2.  Grade 4 neutropenia and thrombocytopenia remain 
exclusions to DLT for this cohort.  Chemotherapy dose reduction will  only be required if DLT criteria 
are met (>14 day delay in course initiation).  Lorlatinib can be continued beyond day 28 when in 
cohort B2 if hematological recovery criteria have not been met. 
 
Minor Changes in risk tables for lorlatinib were updated based on Investigator Brochure dated 
17OCT2019. Corresponding risk tables in the consents were updated.   
 
In addition, instructions for the timing of lorlatinb dosing in Cohort B2 were clarified. 
 
Amendment #9A v 08-20-2021 
 
This protocol amendment updates the study in accordance with the most recent lorlatinib 
Investigator’s Brochure (V11.0). Additionally, language in the eligibility criteria for MIBG non-avid 
disease sites was updated. Clarified platelet count requirements, DLT criteria, and dose 
modifications for patients who continue on cohort B2 without chemotherapy to parallel the 
respective non chemotherapy cohort. Additionally, the age ranges for each cohort were clarified, 
and Cohort B2 was clarified as following a 3+3 design with an expansion cohort opening following 
determination of the RP2D. Details were added on how best overall response will be calculated for 
patients with CR/PR and minor response. The informed consent templates were revised to include 
language for Dr. Mossé’s / NANT’s Disclosure. The neuropsychological testing time points in the 
template consent for Cohort A2 were revised to be consistent with the protocol. SAE reporting 
requirements after a patient comes off protocol therapy was added. An allowance was included to 
continue receiving the remaining lorlatinib investigational product tablets when patient meets off 
protocol therapy criteria for disease progression if it seems to be in the best interest of the patient 
according to the treating physician. In section 4.4, the minimum criteria to be off myeloid growth 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
51 
 
 
factor for patients on cohort B2 prior to starting subsequent course was revised to be consistent 
with section 4.1.4. The restriction on moderate CYP3A inducers was removed from section 4.5 
 
 
The Study Statistician was changed from Susan Groshen, PhD to Yueh-Yun Chi, PhD.  University 
of North Carolina was removed as a participating site.  Minor clarification of soft tissue and bone 
marrow response criteria were made for version 2.0 of response criteria.  
 
Amendment #10 v 02-18-2022 
Background section was edited to include Cohort A2 lorlatinib monotherapy enrollment data. This 
amendment allows for expansion enrollment on Dose level 3A (100mg/day). The statistical 
considerations section was revised accordingly as well. In Section 11.0 Response V2.0; minor 
revisions were made to the non-target soft tissue lesion for clarification purposes. The Bone Marrow 
(BM) Minimal Disease definition in Section 11.0 was revised which was inconsistent with the BM 
response table; the Not Involved definition also had a minor clarification. Minor revision was made 
to footnote numbers 5 and 6 in Required Observations table. Bayley-III testing timelines and 
windows were clarified in section 7.1.2.3. Minor revisions were made to the ICFs that included 
inconsistencies or errors in the lorlatinib risk table.  
 
Amendment #11A 05-06-2022 
Lorlatinib risk information was revised based on Pfizer’s recommendation to include most recent 
observations noted in patients who participated in Study B7461001 (N=327) or Study B7461006 
(N=149) and received lorlatinib 100 mg once daily orally. Section 13.0 was revised to clarify 
language about imaging scan and bone marrow biopsy slide submission for central review 
purposes. The ICFs risk tables were revised accordingly. Additional editorial revisions were made.    
 

 
 
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52 
 
 
3.0 
PATIENT ELIGIBILITY CRITERIA AND REGISTRATION 
 
3.1 
Patient Preparation for Study Entry and Registration 
 
3.1.1 
Patient Registration on Study 
NANT sites are required to complete electronic CRFs on the web-based application Medidata Rave 
in a timely manner. In addition, certain study specific data points will be captured on paper CRFs 
and sent to the NANT Operations Center. This will include all response data that will be entered 
into our central review system for validation of response.  
 
Treatment slots are obtained through the standard NANT reservation process by sending an email 
to NANTrsvp@chla.usc.edu. 
 
When assigned a treatment slot by the NANT Operations Center, sites will initiate the enrollment 
process by completing the Subject Screen form in the web-based application, Medidata Rave. The 
Subject Screen form alerts the NANT Operations Center to all prospective enrollments. Sites 
should send patient signed informed consent and all source documentation confirming eligibility to 
the NANT Operations Center at Children’s Hospital Los Angeles by email to nantcrf@chla.usc.edu 
or if unable to email by FAX at 323-361-1803, Monday through Friday, 8:30am – 5:00pm Pacific 
Time except holidays. 
 
Once all necessary source documentation is received in the NANT Operations Center, sites can 
complete the enrollment process by submitting the eligibility form in Medidata Rave.  The NANT 
Operations Center will verify eligibility and assign a unique NANT registration and study subject 
number in Medidata Rave.  The cohort / dose level (if applicable) for treatment will be assigned by 
the NANT Operations Center at the time of study registration.  Once eligibility is verified, the NANT 
Operations Center will send an email confirming registration and dose level for treatment.  This 
registration email must be received prior to starting any protocol therapy or the patient will be 
declared ineligible.  The registration email will be sent to the treating facilities, Study Chair, Study 
Vice-Chair, and relevant committee members.  The registration steps are summarized in Table 10 
below. 
  
Table 10:  Summary of Registration Steps 
Step 
Process  
Comment 
1 
Treatment slots are assigned based on reservation 
requests processed through the NANT Operations 
Center. 
 
2 
Once notified by NANT Operations Center that a 
treatment slot has been assigned for a patient, site 
completes Subject Screen form in Medidata Rave. 
 
3 
Site sends signed informed consent and all source 
documentation confirming eligibility to NANT 
Operations Center.   
*Email: nantcrf@chla.usc.edu 
*If unable to email documents, fax is 
acceptable.  FAX: (323) 361-1803  
4 
Site completes demographics and eligibility form in 
Medidata Rave in addition to required paper CRFs. 
 
5 
NANT Operations Center verifies eligibility and 
assigns unique NANT registration and study subject 
number in Medidata Rave. NANT Operations Center 
assigns the dose level/cohort for treatment. 
 
6 
NANT Operations Center sends an email confirming 
registration. 
Confirmation sent to the treating facilities, 
Study Chair, Study Vice-Chair, and relevant 
committee members. 
7 
Patient can begin treatment as specified in the 
protocol 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
53 
 
 
A registration worksheet is available on the web site (www.NANT.org) in the data forms packet to 
assist institutions with registration requirements for this protocol. Please contact NANT Operations 
Center at the contact information below for questions on registration.  
 
  
Contact Person:  
 
Research Coordinator  
 
 
 
 
NANT Operations Center 
 
 
 
 
Children’s Hospital Los Angeles 
 
 
 
 
4650 Sunset Blvd, MS #54 
 
 
 
 
Los Angeles, CA 90027 
 
 
 
 
Phone:  (323) 361-5687 
 
 
 
 
FAX:  (323) 361-1803 
 
 
 
 
nantcrf@chla.usc.edu 
 
 
 
 
 
To allow non-English speaking patients to participate in this study, bilingual health services will be 
provided in the appropriate language when feasible. 
 
Timing of Registration and Treatment Initiation: 
Initiation of protocol therapy is required within 1 week of study enrollment. 
 
3.1.2  
Co-Enrollment on NANT 2004-05 
Co-enrollment on NANT 2004-05 (NANT Neuroblastoma Biology Study) is required for all patients 
enrolling on this trial.  Patients are strongly encouraged to submit bone marrow as well as blood 
prior to starting therapy on NANT 2015-02 and continue to submit with each disease evaluation. 
 
IMPORTANT NOTE:  
The eligibility criteria listed below are interpreted literally and cannot be waived.   
 
3.2 
Inclusion Criteria 
 
3.2.1 
Age 
 
Patients must be ≥ 12 months of age at the time of enrollment on the study.  
 
 
3.2.2 
Diagnosis 
Patients must have a diagnosis of neuroblastoma either by histologic verification of neuroblastoma 
and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines. 
 
3.2.3 
ALK Tumor Alterations 
ALK testing will not be performed as part of this trial,but must be completed prior to registration. 
Patients are required to have an activating ALK aberration in their tumor detected by certified 
genetic assay (i.e. CLIA in the US). The report from this test is required to be submitted for eligibility. 
 
Patients with at least one of the following genetic features in their tumor will be considered to have 
an activating ALK aberration:  
a. An ALK activating mutation;  
b. ALK amplification (> 10 signals of the ALK gene);  
c. Presence of any ALK fusion protein that arises from a chromosomal translocation.  
 
ALK expression by immunohistochemistry is NOT acceptable for eligibility. 
 
3.2.4  
Disease Risk Group 
Patients must have high risk neuroblastoma according to COG risk classification at the time of study 
registration.  Patients who were initially considered low or intermediate risk, but then reclassified as 
high risk are also eligible. 
 
 
 
 

 
 
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3.2.5   Response to Prior Therapy (using INRC definitions)  
 
Patients must have at least ONE of the following: 
 
3.2.5.1 Recurrent/progressive disease after the diagnosis of high risk neuroblastoma at any time prior to 
enrollment – regardless of response to frontline therapy. (Note that this excludes patients initially 
considered low or intermediate risk that progressed to high risk disease but have not progressed 
after the diagnosis of high risk neuroblastoma).    
 
3.2.5.2 If no prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma, 
 
3.2.5.2.1 Refractory disease: A best overall response of no response/stable disease since 
diagnosis of high risk neuroblastoma AND after at least 4 courses of induction therapy.  
 
3.2.5.2.2 Persistent disease: A best overall response of partial response since diagnosis of high 
risk neuroblastoma AND after at least 4 courses of induction therapy  
 
3.2.6   Sites of Disease 
Patients must have at least ONE of the following (lesions may have received prior radiation therapy 
as long as they meet the other criteria listed below) based on institutional assessment: 
 
3.2.6.1 Bone Sites 
1. MIBG avid tumors:  patients must meet one of the following criteria: 
a. Patients with recurrent/progressive or refractory disease:  
i. Must have at least one MIBG avid bone site. A biopsy is not required regardless 
of number of MIBG avid sites. 
b. Patients with persistent disease: 
i. If a patient has 3 or more MIBG avid bone lesions, then no biopsy is required.   
ii. If a patient has only 1 or 2 MIBG avid bone lesion sites then biopsy confirmation 
of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site 
present at the time of enrollment is required.  Bone lesions may be biopsied at any 
time point prior to enrollment.  
2. For MIBG non-avid tumors, patients must have at least one FDG-PET avid site and meet the 
following criteria: 
a. Biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma from a lesion at any 
time prior to enrollment of at least one FDG-PET avid site. 
 
3.2.6.2 Bone Marrow  
Any amount of tumor cells in the bone marrow (including neuroblasts, mature and maturing 
ganglion cells) done at the time of study enrollment based on routine morphology and/or 
immunohistochemistry in at least one sample from bilateral aspirates and biopsies.  
 
3.2.6.3 Soft Tissue Sites  
At least one soft tissue lesion that meets criteria for a TARGET lesion as defined by: 
1. SIZE:  Lesion can be accurately measured in at least one dimension with a longest diameter ≥ 10 
mm, or for discrete lymph nodes ≥ 15mm on short axis.  Lesions meeting size criteria will be 
considered measurable. 
2. In addition to size, a lesion needs to meet ONE of the following criteria except for patients with 
parenchymal CNS lesions which will only need to meet size criteria: 
a. For  MIBG avid tumors:  lesion must be MIBG avid and meet one 
of the following criteria:   
i. For patients with recurrent/progressive or refractory disease: 
1. no biopsy is required 
ii.  For patients with persistent disease:   
1. If a patient has 3 or more MIBG avid soft tissue 
lesions, then no biopsy is required. 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
55 
 
 
2. If a patient has only 1 or 2 MIBG avid soft tissue lesion 
sites) then biopsy confirmation of neuroblastoma 
and/or ganglioneuroblastoma in at least one MIBG 
avid site present at the time of enrollment is required.  
Soft tissue lesions may be biopsied at any time point 
prior to enrollment.  
b. For MIBG non-avid tumors patient must have at least one FDG avid site and 
meet the following criteria:  
i. Biopsy 
confirmation 
of 
neuroblastoma 
and/or 
ganglioneuroblastoma from a lesion at any time prior to 
enrollment of at least one FDG-PET avid site. 
 
 
3.2.6.4 At least one non-target soft tissue lesion that is not measurable, but had a biopsy positive for  
neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment or is MIBG avid.  
 
3.2.7 
Performance level  
Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of ≥ 50 (Appendix I). 
 
3.2.8    Prior Therapy 
  
3.2.8.1 Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to study registration. 
 
3.2.8.2 Concomitant Therapy Restrictions 
1. Patients must not be receiving any other anti-cancer agents or radiotherapy. 
2. Patients must not be receiving chronic systemic corticosteroids at doses greater 
than physiologic dosing (inhaled corticosteroids acceptable). 
3. CYP3A4 Inhibitors. The concurrent use of known strong CYP3A inhibitors (eg, 
atazanavir, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, 
ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, voriconazole, 
grapefruit juice or grapefruit/grapefruit-related citrus fruits [e.g., Seville oranges, 
pomelos]) within 12 days prior to the first dose of lorlatinib is not permitted. The 
topical use of these medications (if applicable), such as 2% ketoconazole cream, 
is allowed. Consult the sponsor if in doubt whether a food or a drug falls into any 
of the above categories. 
4. CYP34A Inducers. The concurrent use or anticipated need for drugs that are 
known strong CYP3A4 inducers (e.g., avasimibe, carbamazepine, phenobarbital, 
phenytoin, rifatutin, rifampin, St. John’s Wort), including their administration within 
12 days prior to the first lorlatinib dose is not permitted. Consult the sponsor if in 
doubt whether a food or a drug falls into any of the above categories. 
5. CYP34A Substrates. The concurrent use of CYP3A substrates with narrow 
therapeutic indices (e.g., alfentanil, astemizole*, cisapride*, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl including transdermal patch, pimozide, 
quinidine, sirolimus, tacrolimus, terfenadine* [*withdrawn from US market]) within 
12 days prior to the first dose of lorlatinib is not permitted. 
P-gp Substrates. The concurrent use of drugs which are P-gp substrates with 
narrow therapeutic index, such as digoxin is not permitted at study entry. The use 
of these drugs during the study is not recommended and alternate medications 
should be considered.  
 
3.2.8.3 Prior ALK inhibitor treatment 
1. Patients must not have been previously treated with lorlatinib   
2. Prior therapy with other ALK inhibitors is allowed.  
3. Patients must not have received the therapies indicated below within the specified time 
period prior to registration on this study as follows: 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
56 
 
 
 
 
 
 
Table 11. Prior Therapies List   
Type of Therapy 
Specified Time Period 
Additional Comments 
Myelosuppressive Chemotherapy  
≤ 14 days  
This includes cytotoxic agents given 
on a low dose metronomic regimen 
as well as retinoids. 
 
Biologic Antineoplastic 
≤ 7 days  
Monoclonal Antibodies 
≤ 7 days or 3 half-lives whichever is 
longer, but no longer than 30 days 
(with recovery of any associated 
toxicities). 
Please refer to table posted at 
www.nant.org for definition of half-
lives for specific monoclonal 
antibodies. 
Cellular Therapy (e.g. modified T 
cells, NK cells, dendritic cells, etc.) 
≤ 21 days and with recovery of all 
associated toxicities 
 
Radiation  
Small port radiation 
≤ 7 days 
 
Large field radiation therapy 
≤ 12 weeks 
i.e. total body irradiation, 
craniospinal, whole abdominal, total 
lung, > 50% marrow space 
Other Substantial Bone Marrow 
Radiation 
≤ 6 weeks 
 
131I-MIBG therapy 
≤ 6 weeks 
 
Hematopoietic Stem Cell Transplant 
Autologous Stem Cell Infusion 
Following Myeloablative Therapy 
≤ 6 weeks 
Patients who have received an 
autologous stem cell infusion to 
support non-myeloablative therapy 
(such as 131I-MIBG) are eligible at 
any time as long as they meet the 
other criteria for eligibility. 
Any other investigational agents 
(covered under another IND) 
≤ 14 days 
 
 
3.2.9 
Organ Function Requirements 
 
3.2.9.1 Hematologic Function:   
Patients must meet the following hematologic criteria for enrollment regardless of bone marrow 
disease involvement: 
1. ANC ≥750/uL (no short-acting hematopoietic growth factors ≤ 7 days of blood draw 
documenting eligibility and no long-acting hematopoietic growth factors ≤ 14 days of blood 
draw documenting eligibility); and 
2. Platelet count: 
i. 
Cohorts A1, A2, and B1 (with omission of chemotherapy): ≥ 50,000/µl, 
transfusion independent (no platelet transfusions or platelet growth factors ≤ 7 
days of blood draw documenting eligibility). 
ii. 
Cohort B2 (with chemotherapy): ≥ 75,000/µl, transfusion independent (no 
platelet transfusions or platelet growth factors ≤ 7 days of blood draw 
documenting eligibility). 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
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3.2.9.2 Renal Function  
1. Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 
ULN for age (see below): 
 
Table 12. Serum Creatinine Criteria  
Age 
Maximum Allowable Serum Creatinine 
< 5 years 
0.8 mg/dL 
> 5 and < 10 years 
1.0 mg/dL 
>10 and < 15 years 
1.2 mg/dL 
> 15 years 
1.5 mg/dL 
 
3.2.9.3 Liver Function 
1. Total bilirubin ≤ 1.5 x ULN for age; and, 
2. SGPT (ALT) ≤ 135 U/L (≤ 3x ULN).  Note that for ALT, the upper limit of normal for all sites is 
defined as 45 U/L. 
 
3.2.9.4 Pancreatic Function 
1. 
Serum total amylase ≤ 1.5 xULN 
2. 
Serum Lipase ≤ 1.5 xULN 
 
3.2.9.5 Neuropsychological Function  
Patients must exhibit ≤ grade 1 as defined by CTCAE v4 of the following nervous system disorders 
and  psychiatric disorders listed below based on physician assessment: 
a. Nervous System Disorders - Amnesia, Cognitive Disturbance, Concentration 
Impairment, Depressed level of consciousness, Memory impairment   
b. Psychiatric Disorders - Agitation, Anxiety, Confusion, Delirium, Depression, Euphoria, 
Hallucinations, Mania, Personality change, Psychosis, Restlessness 
 
3.2.9.6 Cardiac Function 
1. Corrected QTc ≤ 480 msec 
1. Patients with an EKG PR interval within the ULN for age (see Table 13 below adapted from Park 
MK, Guntheroth WG: How to Read Pediatric ECGs, ed 2. Chicago, Year Book Medical 
Publishers, 1987). 
 
Table 13: PR Interval (ULN) Corresponding to Age  
Age (in years) 
PR Interval (in sec) 
1 – 2 
≤ 0.15 
3 – 7 
≤ 0.17 
8 – 11 
≤ 0.18 
12 – 15 
≤ 0.19  
≥16  
≤ 0.20 
 
3.2.9.7  Pulmonary Function 
 No evidence of dyspnea at rest, no exercise intolerance.   
 
3.2.9.8  Reproductive Function 
All post-menarchal females must have a negative serum or urine beta-HCG ≤ 7 days prior to 
registration. Male and female subjects of reproductive age and childbearing potential must agree to 
use two acceptable methods of birth control (i.e., intra-uterine device, diaphragm with spermicide, 
condom with spermicide, or abstinence) or to abstain from heterosexual intercourse for the duration 
of their participation in the study.  If a hormonal method of contraception is unavoidable, then a 
condom must be used in combination with the hormonal method.  

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
58 
 
 
 
3.3 
Exclusion Criteria 
3.3.1 
Pregnancy, breast feeding, or unwillingness to use effective contraception during the study will not 
be entered on this study due to risks of fetal and teratogenic adverse events. 
3.3.2 
Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring 
requirements of the study. 
 
3.3.3 
Patients with disease of any major organ system that would compromise their ability to withstand 
therapy. 
 
3.3.4 
Patients must not have received prior allogeneic stem cell transplant. 
 
3.3.5  
Patients who are on hemodialysis. 
3.3.6 
Patients with an active or uncontrolled infection. Patients on prolonged antifungal therapy are still 
eligible if they are culture negative, afebrile, and meet other organ function criteria.  
3.3.7 
Patients with known history of human immunodeficiency virus (HIV) infection, hepatitis B, or 
hepatitis C. Testing is not required in the absence of clinical findings or suspicion.  
3.3.8 
Patients with known history of acute or chronic severe psychiatric disorders.  
3.3.9 
Patients with current history of suicidal ideation, and history of suicide attempt in their lifetime. 
3.3.10   Patient declines participation in NANT 2004-05.  In limited situations an institution may be granted 
a waiver from biology study participation. 
 
3.4 
Regulatory 
 
3.4.1 
Informed Consent 
The patient and/or the patient’s legally authorized guardian must acknowledge in writing that consent 
to become a study subject has been obtained, in accordance with institutional policies approved by 
the US Department of Health and Human Services. 
 
3.4.2 
Protocol Approval 
All institutional, FDA, and NCI requirements for human studies must be met. 

 
 
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59 
 
 
4.0 
TREATMENT PROGRAM 
 
4.1 
Treatment Overview 
 
Drug doses should be adjusted based upon height and weight obtained ≤ 7 days prior to the start 
of each course. One course consists of 4 weeks of therapy (28 day course).  
 
Patients who have not been previously treated with an ALK inhibitor (“ALKi naïve”) and patients 
who have been previously treated with an ALK inhibitor (except for lorlatinib) are eligible for this 
study and all treatment cohorts. Please refer to the experimental design schema section of the 
protocol for revisions made to the treatment overview with the activation of Amendment 7.  
 
Disease evaluation should be performed on week 4 of courses 2, 4, 6 and every 4th course 
subsequent to course 6 in addition to end of therapy. Patients with stable disease or who are having 
clinical benefit from lorlatinib in cohorts A1, A2 and B1 may continue receiving protocol therapy 
provided that the patient meets criteria for starting subsequent courses and does not meet any 
criteria for removal from protocol therapy or off-study criteria. Patients on cohort B2 may continue 
to receive protocol therapy for up to 24 courses with chemotherapy or may stop combination 
chemotherapy after 4 cycles and continue on single agent lorlatinib at the same dosing indefinitely 
provided the patient meets criteria for starting subsequent courses and does not meet criteria for 
removal from protocol therapy or off-study criteria.  
 
4.1.1  
Lorlatinib (PF-06463922) 
 
 
 
 
 
 
 
 
 
 
 
*Disease Evaluation performed after Day 22 of Week 4 of Courses 2, 4, and 6 and every 4th course 
thereafter in addition to end of therapy.  
 
If a patient vomits within 20 minutes of dose administration, the patient should be re-dosed. If the 
patient vomits after the second dose, the patient should not be re-dosed again. If a patient vomits 
more than 20 minutes from dose administration, the patient should not be re-dosed. Refer to 
Section 6.1 for drug administration guidelines. For patients who are unable to swallow the tablets 
whole, refer to the Investigational Product Manual for dispersed tablet compounding. 
 
For the oral lorlatinib tablets, the dose should be rounded according to the calculation in Appendix 
III.  
 
 
 
 
 
 
 
 
 
Table 14a: Cohorts A1, A2, B1 Treatment Course 
Week 1 
Week 2 
Week 3 
Week 4* 
Days 1 - 7 
Days 8 - 14 
Days 15 - 21 
Days 22 - 28 
 
Lorlatinib  
 

 
 
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60 
 
 
Table 14b: Cohort B2  Treatment Course 
Week 1 
Week 2 
Week 3 
Week 4 
Day 1 
Day 2 
Day 
3 
Day 4 
Day 5 
Day 
6 
Day 
7 
Days 
8-14 
Days 
15 -21 
Days 
22-28 
 
Lorlatinib  
 
CPM 
CPM 
CPM 
CPM 
CPM 
 
 
 
 
 
TOPO 
TOPO 
TOPO 
TOPO 
TOPO 
MGF 
 
 
 
 
     CPM: Cyclophosphamide 
 
 
 
    TOPO: Topotecan 
     MGF: Myeloid growth factor 
 
The following conventional chemotherapy treatments are for patients registered in cohort B2 only.     
 
4.1.2 
Cyclophosphamide 
Cyclophosphamide 250mg/m2/day will be administered as a 30 minute IV infusion on days 1-5 of 
each course. 
 
Pre-hydration and post-hydration are to be provided according to institutional standards. Mesna 
may be delivered according to institutional standards but is not mandated nor routinely used for 
this cyclophosphamide dose. 
 
4.1.3 
Topotecan 
Topotecan 0.75mg/m2/day will be administered as a 30 minute IV infusion immediately following 
cyclophosphamide on days 1-5 of each course. 
 
4.1.4 
Myeloid Growth Factor 
Filgrastim (5 mcg/kg/day) is to be given with each course beginning 24-48 hours following the 
completion of cyclophosphamide and topotecan and continued through post-nadir count recovery 
with an ANC > 2000/mm3. Filgrastim must be discontinued at least 24 hours prior to the start of the 
next course of therapy.   
 
Pegfilgrastim (100 mcg/kg; 6 mg maximum dose) may be substituted and is given one time at 24-
48 hours from completion of cyclophosphamide and topotecan. 
  
4.2 
Dose Escalation Schedule 
Cohort A1 of this study will identify a recommended phase 2 dose (RP2D) of lorlatinib as a single 
agent in pediatric patients ≥ 12 months and < 18 years of age. All toxicities observed during the 
first course of treatment (day 1 through day 28) and only neuropsychological toxicities observed in 
the second course of treatment will be assessed to define the maximum tolerated dose (MTD) and 
guide dose escalation.  The lorlatinib dose will be escalated using the standard 3 + 3 phase 1 trial 
design (Section 10) per the following dose escalation schema (Table 15a-d). 
 
NOTE:  Patients > 18 YOA or whose BSA is ≥ 1.73m2 will be assigned to cohort A2 and receive 
the adult RP2D (100mg) when Cohort A1 is enrolling Dose levels 1-3. At Dose Level 3 (75 
mg/m2/day) of the dose escalation cohort A1 of the trial, patients < 18 YOA and whose BSA is 
between 1.43m2 and 1.72m2, will also be assigned to Cohort A2 and also receive the adult RP2D 
(100mg) and not be involved in the dose escalation portion of this trial. After activation of 
Amendment 4, patients on cohort A2 will receive lorlatinib at a starting dose of 150mg daily and will 
follow a 3+3 dose escalation design with dose levels defined in Table 15b.  With activation of 
Amendment 7, the dose of lorlatinib at Dose Level 5 in Cohort A1 will not be capped for “large” 
patients who are < 18 years of age. 
 

 
 
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61 
 
 
Following activation of Amendment 7, the B2 chemotherapy combination cohort will open to 
patients < 18 YOA at dose level 4B and enroll concurrently with cohort A1 dose level 5 and cohort 
A2 dose level 4A. Patients on B2 will receive lorlatinib at the starting dose of 95 mg/m2/day with 
fixed dosing of topotecan and cyclophosphamide (Table 15c-d.). Lorlatinib should be taken at least 
1 hour prior to chemotherapy. Once the RP2D is determined for adults on A2, then B2 will also 
open to patients > 18 to ≤ 30 YOA at the RP2D with no dose escalation. Patients > 30 YOA will 
enroll on the A2 expansion cohort with single agent lorlatinib at the RP2D. 
 
Table 15a: Lorlatinib Dose Escalation Schema  
for patients on Cohort A1 
Dose Level 
Lorlatinib  
mg/m2/day orally 
-1 
30  
1 (Starting Dose) 
45  
2 
60  
3 
75  
4 
95  
5 
115  
 
The starting dose of lorlatinib represents approximately 75% of the adult RP2D of 100mg once 
daily.  Dose level 2 corresponds approximately to the adult RP2D (for a BSA of approximately 
1.67m2), Dose level 3 is approximately ~125% of the adult RP2D, Dose level 4 is approximately 
160% of the adult RP2D, and Dose level 5 is approximately 190% of the adult RP2D. 
 
Table 15b: Lorlatinib Dose Escalation Schema  
for patients on Cohort A2 
Dose Level 
Lorlatinib  
mg/day orally 
Pre amendment 4 Dose Assignment  
Dose level 3a  
100  
Post amendment 4 Dose Assignment 
Dose level 4a 
150  
 
 
Table 15c. Lorlatinib Dose Escalation Schema  
for patients < 18 YOA on Cohort B2 
Combination Dose Level 
Lorlatinib 
mg/m2/day orally 
(max dose) 
Topotecan 
mg/m2/day IV 
Cyclophosphamide 
mg/m2/day IV 
3B 
75 
(100 mg max) 
0.75 
250 
4B 
(Starting Dose) 
95 
(150 mg max) 
0.75 
250 
5B 
115 
(200 mg max) 
0.75 
250 
 
 

 
 
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Table 15d. Lorlatinib Dose Schema  
for patients > 18 YOA on Cohort B2 
Combination Dose Level 
Lorlatinib 
mg/m2/day orally 
(max dose) 
Topotecan 
mg/m2/day IV 
Cyclophosphamide 
mg/m2/day IV 
-1 RP2D 
-1 RP2D  
0.75 
250 
RP2D 
(Starting Dose) 
RP2D 
0.75 
250 
 
The dose level will be assigned at the time of registration for patients enrolling on cohort A1, and 
post amendment 4 on cohort A2, and post amendment 7 on cohort B2.  
- 
For patients enrolled after activation of Amendment 4 of dose escalation: No more than two 
patients can simultaneously be enrolled on Course 1 of therapy in each of Cohorts A1 and A2.  
- 
Following Amendment 4 during dose escalation: due to concern about possible delayed 
neurocognitive toxicities, the DLT evaluation period has been extended to include both Course 
1 and Course 2, with any DLT during Course 1 but only neurocognitive DLTs during Course 2 
counting for dose escalation/de-escalation decisions.   
- 
Following Amendment 7:  For cohort B2 evaluation of DLTs will occur during Course 1, since 
single agent toxicity for all DLTs will be available and chemotherapy combination is not likely to 
exacerbate neurocognitive  toxicity.  In addition, standard 3+3 rules will be used for toxicity 
evaluation and a maximum of 3 patients simultaneously can be enrolled on dose level 4B and 
when escalated to dose level 5B.   
  
4.3  
Definition of Dose-Limiting Toxicity (DLT) 
 
Toxicity will be graded using the CTCAE criteria, version 4. The CTCAE provides descriptive  
 
terminology and a grading scale for each adverse event listed. A copy of the CTCAE can be  
 
downloaded from the CTEP home page (http://ctep.cancer.gov).  Any dose-limiting toxicity  
 
should be reported immediately through the NANT Operations Center to the Study Chair.  
 
4.3.1  
Definition of Unevaluable for Dose Escalation 
Refer to Section 10.1.1 for the definition of “evaluable for DLT”.  
 
4.3.2  
Definition of Dose-Limiting Toxicity 
DLT is defined as any of the following events that are possibly, probably or definitely attributable to 
protocol therapy.  Refer to Table 16a for dose modifications.  
 
Note:  Although all such events will be recorded, only those DLT’s occurring in the 1st course of 
therapy will be counted in the decisions to dose escalate, expand, or de-escalate – with one 
exception:  for Cohorts A1, A2, and B1 (but not B2), neurocogntive DLT’s in the 2nd course will be 
counted in the decisions to dose escalate, expand, or de-escalate. Patients on cohort B2 who no 
longer receive chemotherapy should follow DLT and dose modifications criteria as specified for 
lorlatinib monotherapy cohorts.     
 
Non-Hematological DLT: 
1. Any Grade 3 or Grade 4 non-hematological toxicity attributable to the lorlatinib will be 
considered a DLT except for the following toxicities: 
a. Grade 3 nausea and vomiting, anorexia or dehydration resolving to ≤ Grade 2 
within 72 hours  
b. Grade 3 AST, ALT, or GGT liver enzyme elevations that return to levels that 
meet initial eligibility criteria ≤ 7 days. If grade 3 liver enzyme elevation occurs, 
the next dose of drug should be held and liver enzymes rechecked at least twice 
weekly of initial date of grade 3 abnormalities. Note: For the purposes of this 
study the ULN for ALT is defined as 45 U/L. 

 
 
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63 
 
 
c. Grade 3 fever or infection  
d. Grade 3 febrile neutropenia cohort B2.  Note: For cohorts A1, A2, B1 febrile 
neutropenia is a DLT if attributable to lorlatinib monotherapy and if lorlatinib is 
withheld > 7 days due to toxicity  
e. Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia 
responsive to oral supplementation 
f. 
Grade 3 high cholesterol or triglycerides if responsive (to ≤ Grade 2) with statin 
treatment (See Section 5.3 for statin therapy options) 
g. Grade 3 weight gain  
h. Grade 3 hyperglycemia if responsive (to < Grade 2) with dietary modification* 
i. 
Grade 3 or Grade 4 obesity 
2. 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 
3. Recurrence of grade 2 neuropsychological effects  
4. Grade 2 radiologically confirmed pancreatitis 
5. Recurrence of grade 2 first degree symptomatic heart block 
6. Grade 1 second degree (Mobitz Type 1 or 2) asymptomatic heart block  
7. Any non-hematological toxicity that results in delay in start of subsequent course by > 14 
days 
8. Any non-hematological toxicity that requires the patient to miss more than 25% of drug 
in a course will be considered a DLT 
 
* Grade 3 glucose intolerance is still considered a DLT  
 
Hematological DLT:  
For A1, A2 and B1, and B2 (without chemotherapy) hematological dose-limiting toxicity is defined 
as: 
1. Grade 4 thrombocytopenia or Grade 4 neutropenia > 7 day duration (see Table 16a for 
dose modifications) 
2. Delay in the start of subsequent course by > 14 days due to ongoing thrombocytopenia 
or neutropenia, in the absence of bone marrow disease progression seen on clinically-
indicated bone marrow biopsy (if performed) 
 
For B2 (with chemotherapy), hematological dose-limiting toxicity is defined as: 
1. Delay in the start of subsequent course by > 14 days due to ongoing thrombocytopenia 
or neutropenia, in the absence of bone marrow disease progression seen on clinically-
indicated bone marrow biopsy after the first dose reduction of cyclophosphamide and 
topotecan (see Table 16a for dose modification).  
 
Patients who experience dose-limiting neutropenia and/or thrombocytopenia will have these events 
reviewed by the SMC to discuss attribution (bone marrow disease [baseline and subsequent (if 
performed and clinically indicated] versus study drug). Patients with bone marrow disease 
progression will not be considered to have dose-limiting hematological toxicities. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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64 
 
 
4.3.3 
Dose Modifications and Supportive Care for Toxicities Attributable to Protocol Treatment  
 
Table 16a. Dose Modifications for Toxicities (possibly, probably, definitely) attributable to 
Lorlatinib (Cyclophosphamide, Topotecan for Cohort B2) 
 
Event 
Action 
NEUROPSYCHOLOGICAL EFFECTS  - See Section 3.2.9.5 for list of CNS Function requirements 
Grade 1 
• 
Continue lorlatinib at same dose 
Grade 2 
• 
Withhold lorlatinib until recovery to Grade ≤ 1 and restart protocol therapy at same 
dose* 
• 
If toxicity reoccurs a second time, withhold drug until recovery to Grade ≤1, and restart 
protocol therapy at the next lower dose level* 
• 
If toxicity reoccurs a third time, discontinue drug permanently 
Grade 3 
• 
Withhold drug until recovery to Grade ≤ 1 and restart protocol therapy at the next lower 
dose level* 
• 
If toxicity reoccurs, discontinue drug permanently 
Grade 4  
• 
Discontinue drug permanently  
*Repeat testing will be performed ≤ 7 days of withholding drug and then weekly to monitor for recovery to Grade ≤ 1 (See Section 
7, Table 24 for neuropsychological testing by age). Patients < 3 years of age will only have repeat parental testing. Appropriate 
radiologic and laboratory monitoring should be pursued at the investigator’s discretion to rule out acute non-related events. 
PANCREATITIS  
Grade 1 
• 
NONE  
Grade 2 
• 
If elevated enzymes are observed in the absence of radiological findings of 
pancreatitis: continue at same dose level. Repeat lipase and amylase (pancreatic 
isoenzymes required) weekly until total serum amylase is within normal institutional 
limits 
• 
If radiologically confirmed pancreatitis: withhold drug. Repeat radiology and lipase, 
amylase weekly and if returned to baseline then resume treatment at the next lower 
dose level 
• 
If radiologically confirmed pancreatitis reoccurs, remove patient from protocol therapy 
Grade 3 - 4 
• 
Discontinue drug permanently  
ELEVATED TOTAL CHOLESTEROL OR TRIGLYCERIDES - See table 17 for statin therapeutic recommendations 
Grade 1 
• 
Continue lorlatinib at same dose 
• 
Consider introducing use of a statin or other lipid lowering agent as appropriate based 
on investigator’s medical judgment 
Grade 2 
• 
Continue lorlatinib at same dose  
• 
If persistent, introduce the use of a statin or other lipid lowering agent as appropriate 
Grade 3 
• 
Continue lorlatinib at same dose 
• 
Introduce use of a statin or other lipid lowering agent as appropriate, or increase dose 
of ongoing statin/lipid lowering agent, or change to a new agent 
• 
Recheck chol/tgl once a week 

 
 
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65 
 
 
Grade 4 
• 
Withhold lorlatinib  
• 
Introduce use of a statin or other lipid lowering agent as appropriate, or increase dose 
of ongoing statin/lipid lowering agent, or change to a new agent 
• 
Recheck chol/tgl twice a week 
• 
When toxicity is Grade ≤ 3, reduce dose by one dose level. 
• 
If grade 4 toxicity reoccurs, withhold lorlatinib again and follow same supportive care 
guidelines above 
• 
When toxicity is Grade ≤ 3, reduce dose to the next lower dose level; if patient is 
already on dose -1 level, discontinue drug permanently 
 
WEIGHT GAIN ASSOCIATED CO-MORBIDITIES   
Increased 
Hemoglobin 
A1C  
OR  
Grade 2 fasting 
hyperglycemia 
• 
HbA1C level between 5.8 - 6.5 range is considered prediabetes 
• 
For levels > 5.7 refer to endocrinology consult for observation and monitoring of blood 
sugar levels as clinically indicated 
• 
Refer for Nutrition consult with recommendations for dietary modification 
• 
Lifestyle modification with increased exercise recommended 
High Blood 
Pressure   
• 
Assess triplicate (3x) blood pressure measurements if blood pressure >95% threshold 
for age, height and gender  
• 
If blood pressure measurements continue to exceed 95% threshold consider anti-
hypertensive agents  
PROLONGED QTC INTERVAL 
Grade 1 
• 
Assess electrolytes and concomitant medications 
• 
Correct any electrolyte abnormalities 
• 
Continue lorlatinib at same dose level 
 
 
 
 
Grade 2 
• 
Assess electrolytes and concomitant medications 
• 
Correct any electrolyte abnormalities 
• 
Continue lorlatinib at same dose level 
 
 
 
 
Grade 3 
• 
Withhold lorlatinib.  Repeat ECG daily until it returns to < 481 ms   
• 
Reduce dose by one dose level and resume protocol therapy 
• 
Repeat ECG 7 and 14 days after dose resumption 
• 
If grade 3 toxicity recurs,  discontinue lorlatinib permanently 
 
 
Grade 4 
• 
Discontinue lorlatinib permanently 
 
 
 
 

 
 
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66 
 
 
ELEVATED LIVER ENZYMES (ALT, AST, GGT) 
Grade 1 - 2 
• 
NONE  
Grade 3  
Cohort A1, A2, B1 and B2  
• 
Withhold lorlatinib until resolution of toxicity to < Grade 1 (or baseline, whichever is 
higher) then resume at same dose if resolved ≤ 7 days. 
• 
Recheck liver enzymes at a minimum within 5 days of initial date of occurrence of 
Grade 3 abnormality 
• 
If not resolved in 7 days post dose hold, once resolved, lorlatinib will then be resumed 
at one dose level below assigned initial dose level. Continue cyclophosphamide and 
topotecan at the same dose (if applicable).    
Grade 4 
Cohort A1, A2, B1 and B2  
• 
Withhold lorlatinib until resolution of toxicity to < Grade 1 (or baseline, whichever is 
higher) 
• 
Recheck liver enzymes at a minimum within 5 days of initial date of occurrence of 
Grade 3 abnormality 
• 
Lorlatinib will then be resumed at one dose level below assigned initial dose level 
Continue cyclophosphamide and topotecan at the same dose (if applicable).    
FEBRILE NEUTROPENIA  
Grade 1 - 2 
• 
NONE 
Grade 3 - 4 
For Cohorts A1, A2, B1  
• 
Withhold lorlatinib until resolution of toxicity to < Grade 1 (or baseline, whichever is 
higher) 
• 
If lorlatinib is withheld > 7 days, lorlatinib will then be resumed at one dose level below 
assigned initial dose level. If toxicity resolves < 7 days from withholding lorlatinib, 
restart lorlatinib at the same dose level.  
For Cohort B2 (with chemotherapy) - Grade 3 is not a DLT.  Continue as prescribed. 
Grade 4 is considered a DLT.  
• 
Withhold lorlatinib until resolution of toxicity to < Grade 1 (or baseline, whichever is 
higher) 
• 
Continue lorlatinib at the same dose level. Reduce topotecan and cyclophosphamide 
doses by 25%. If toxicity reoccurs despite chemotherapy dose reduction, reduce 
lorlatinib by one dose level below the RP2D. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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THROMBOCYTOPENIA OR NEUTROPENIA  
Grade 1 - 3 
• 
NONE 
Grade 4 
Cohort A1, A2, B1  
• 
Withhold lorlatinib until resolution of toxicity to < Grade 1 (or baseline, whichever is 
higher). 
• 
Cohort A1/A2: Resume lorlatinib at one dose level below assigned initial dose level 
• 
Cohort B1: Resume lorlatinib at one dose level below the RP2D established in cohort 
A1  
 
Cohort B2 (with chemotherapy):  
 
• 
Continue lorlatinib at the same dose level. If the patient experiences dose limiting 
neutropenia or thrombocytopenia (delay >14 days) reduce topotecan and 
cyclophosphamide doses by 25% in the next course. . Lorlatinib should be continued at 
the same dose past day 28, during the period of hematologic recovery.If toxicity 
reoccurs despite chemotherapy dose reduction, reduce lorlatinib by one dose level 
below the RP2D. 
 
For ALL COHORTS 
• 
Patients with bone marrow disease progression confirmed with clinically indicated bone 
marrow biopsy (if performed) will not be considered a DLT. 
Any Grade  
For Cohorts A1, A2, B1 
• 
Delay in the start of subsequent course by > 14 days due to ongoing thrombocytopenia 
or neutropenia, in the absence of bone marrow disease progression seen on clinically-
indicated bone marrow biopsy (if performed) should resume lorlatinib at one dose level 
below assigned initial dose level for patients on Cohort A1 and A2. For patients in 
cohort B1, lorlatinib will be resumed at one dose level below the RP2D established in 
cohort A1. 
• 
If a patient experiences a recurrent delay despite the dose reduction of lorlatinib due to 
ongoing thrombocytopenia and neutropenia, the patient must be removed from protocol 
therapy.  
For Cohort B2 (with chemotherapy) 
• 
Patients who experience a delay in the start of subsequent course > 14 days due to 
ongoing thrombocytopenia or neutropenia (as defined in section 4.3.2),  in the absence 
of bone marrow disease progression seen on clinically-indicated bone marrow biopsy 
(if performed)  should resume subsequent courses at the same lorlatinib dose level. 
Reduce topotecan and cyclophosphamide doses by 25%. Lorlatinib could be continued 
at the same dose past day 28, during the period of hematologic recovery as long as 
drug is still available for the course. 
• 
Patients with recurrent delay in the start of subsequent course by > 14 days due to 
ongoing thrombocytopenia or neutropenia despite the topotecan/cyclophosphamide 
dose reduction should have lorlatinib held until patient is able to meet criteria. At the 
start of the subsequent course, patient should have the lorlatinib dose reduced by one 
dose level.   
• 
If a patient experiences a recurrent delay despite the dose reduction of the 
cyclophosphamide/topotecan and lorlatinib due to ongoing thrombocytopenia and 
neutropenia, the patient must be removed from protocol therapy. 
 
 
 
 
 
 

 
 
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GENERAL DOSE MODIFICATIONS FOR ALL DLTS 
For Cohorts A1, A2, B1 and B2 
• 
Withhold lorlatinib until resolution of toxicity to < Grade 1 (or baseline, whichever is higher)   
• 
If the toxicity resolves to meet eligibility requirements or baseline ≤ 21 days of study drug interruption, 
patient may resume lorlatinib treatment at one dose level below assigned initial dose level. For patients in 
cohort B1, lorlatinib will be resumed at one dose level below the RP2D established in cohort A1. Patients 
in cohort B2 may resume lorlatinib at the next lower dose level and continue cyclophosphamide and 
topotecan at the same dose.  
• 
Patients already receiving therapy at dose level -1 at the time of initial DLT will be removed from protocol 
therapy. 
• 
Doses reduced for toxicity will not be re-escalated, even if there is minimal or no toxicity with the reduced 
dose.  
• 
If toxicity does not resolve to meet initial eligibility criteria or baseline ≤ 21 days of drug discontinuation, the 
patient must be removed from protocol therapy. 
• 
If the same toxicity reoccurs at the reduced dose level, patient must be removed from protocol therapy. For 
patients in cohort B2, if the attribution to lorlatinib is undetermined, cyclophosphamide and topotecan must 
be reduced to 75% and lorlatinib must be reduced to the next lower dose level.  However, if the DLT 
reoccurs a third time, patient will be removed from protocol therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table 16b. Dose Modifications for Prolonged PR Interval 
 
 
4.3.3.1 Hyperlipidemia Supportive Care - Lipid Lowering Therapy  
In the lorlatinib Phase 1/2 Study 
B7461001, hypercholesterolemia was the most common AE reported. Elevations in lipids usually begin in 
the first few courses and, if statins are not introduced, can rise to Grade 3 levels by the next treatment 
course. Therefore, the suggested management is to consider a statin for Grade 1 elevations in either 
cholesterol or triglycerides and to increase the statin dose if adequate control is not obtained, as outlined 
in the below Table 17.  
 
Members of the statin class of agents are differentially sensitive to CYP3A4, and the following table 
may be used to facilitate management of elevated lipid levels. Of note, muscle toxicity (from myalgia 
to rhabdomyolysis) is a documented side effect of certain statin therapy. This risk is increased with 
concurrent use of medications that inhibit CYP3A4, especially when given with statins that are 
CYP3A4 substrates. In randomized controlled trials, the incidence of statin myopathy was ~1.5–
5.0% (1). One study showed that the most hydrophilic statins were least likely to cause myalgia, 
whereas the most lipophilic ones were most likely to be associated with muscular adverse effects 
(2). Therefore, if myalgias occur in a patient being treated for hypercholesterolemia with a statin on 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
1st Degree 
Heart 
Block 
 
 
Asymptomatic  
 
• 
No dose hold or 
reduction needed.  
• 
Assess concomitant 
medications.  
• 
Monitor closely by 
obtaining ECG within 72 
hours, even if 
unscheduled.  
• 
Instruct patient to call if 
symptoms develop that 
may be related to heart 
block. 
• 
assess weekly until 
resolution 
Symptomatic  
 
• 
Withhold dose.  
• 
Assess concomitant 
medications.  
• 
Monitor closely by obtaining 
ECG within 72 hours and re-
assess symptoms and PR-
interval.  
• 
Restart at same dose when 
symptoms resolve.  
• 
If symptoms reoccur, hold 
study drug, repeat ECG 
within 72 hours and when 
symptoms resolve, restart at 
reduced dose.  
• 
If symptoms reoccur a third 
time, remove patient from 
protocol therapy.  
N/A 
N/A 
N/A 
2nd Degree 
Heart 
Block 
Mobitz Type 
1 or 2 
 
Asymptomatic 
 
• 
Withhold dose.   
• 
Assess concomitant 
medications. 
• 
Monitor closely by 
obtaining ECG within 72 
hours, even if 
unscheduled.  
• 
When subsequent ECG 
does not show 2nd 
degree heart block, 
restart at reduced dose.  
Symptomatic 
 
• 
Withhold dose.  
• 
Refer for cardiac observation 
and monitoring and 
cardiology consult.  
• 
Assess concomitant 
medications 
• 
Monitor closely by obtaining 
ECG within 72 hours, even if 
unscheduled.  
• 
When symptoms resolve, 
restart at reduced dose. 
Symptomatic 
and incompletely 
controlled 
 
 
• 
Remove from 
protocol 
therapy 
 
Life 
Threatening 
 
 
 
• 
Remove 
from 
protocol 
therapy  
Death 
 
 
 
 
 
N/A  
Complete 
Heart 
Block 
 
N/A 
Non-urgent intervention 
indicated 
 
• 
Remove from protocol 
therapy.  
• 
Refer for cardiac observation 
and monitoring.   
Symptomatic 
and incompletely 
controlled 
• 
Remove from 
protocol 
therapy 
Life 
Threatening 
 
• 
Remove 
from 
protocol 
therapy 
Death 
 
 
 
N/A 

 
 
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this trial, please review concurrent medications and laboratory testing and consider replacing the 
statin with a different statin that is less lipophilic and less of a CYP substrate (See Table 17. 
 
Table 17: Statin Usage 
STATIN 
CYP3A 
Lipophilicity 
Potential Effect* of 
Lorlatinib on  
Statin AUC 
Recommendation 
About Statin 
Selection and Dose** 
Rosuvastatin 
(Crestor) 
Not a substrate 
No 
No change 
expected 
Recommended         
No dose change 
Pravastatin 
(Pravachol) 
Substrate 
No 
30-40% decrease in 
AUC 
Consider increasing the 
pravastin dose 
Pitavavastatin 
(Livalo) 
Not a substrate 
Yes 
No change 
expected 
No dose change 
Fluvastatin (Lescol) 
Substrate 
No 
~25 % decrease in 
AUC 
No dose change 
Atorvastatin (Lipitor) 
Substrate 
Yes 
4 % decrease in 
AUC 
Consider increasing the 
atorvastatin dose (e.g., 
10 -->20 mg) 
Simvastatin (Zocor) 
SENSITIVE 
Substrate 
Yes 
50-80% decrease in 
AUC 
Selection not 
recommended 
Lovastatin (Mevacor, 
Altocor) 
SENSITIVE 
Substrate 
Yes 
50-80% decrease in 
AUC 
Selection not 
recommended 
*Estimated based on the reported effect of strong and moderate CYP3A inducers on statins. AUC: area 
under the plasma concentration-time curve. 
** Dose adjustment to be based on changes in cholesterol levels (e.g., worsening by 1 CTCAE grade level). 
 
4.3.3.2 Peripheral Neuropathy Supportive Care 
Treatment with vitamin B1 and vitamin B6 and medications for pain associated with peripheral 
neuropathy (e.g. gabapentin or pregabalin) may provide symptom relief in some cases of peripheral 
neuropathy.  
 
 
4.3.3.3 Peripheral Edema Supportive Care  
Compression stockings, leg elevations, and lifestyle modifications, such as increased exercise and 
limiting dietary salt, should initially be considered in patients with low grade edema before 
commencing with dose modifications. These conservative measures in combination with diuretics 
(usually furosemide) have shown to be effective in the management of edema in adult studies. 
 
4.4       Treatment Duration and Criteria to Start Next Treatment Course 
In the absence of disease progression or toxicity that necessitates drug discontinuation, patients 
may receive protocol therapy indefinitely unless they are on Cohort B2.  Patients who are on Cohort 
B2 can receive up to 24 courses with chemotherapy or may stop combination chemotherapy after 
4 cycles and continue on single agent Lorlatinib at the same dosing (or at the RP2D, when 
determined) indefinitely provided the patient meets criteria for starting subsequent courses and 
does not meet criteria for removal from protocol therapy or off-study criteria. Patients experiencing 
dose-limiting toxicity (DLT) may continue to receive therapy modified as described in Section 4.3. 
 
Criteria to start treatment course 2 and all subsequent courses of therapy - patients must show no 
clinical or radiographic evidence of disease progression and must meet renal, hepatic, CNS and 
other organ function requirements listed in section 3.2.9.2 – 3.2.9.8 except for hematological and 

 
 
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QTc criteria listed below. NOTE: Cardiac evaluations should only be repeated per Required 
Observations, Table 23.  
 
Patients must meet the following hematologic criteria for subsequent courses: 
1. ANC: ≥750/uL  
a. For Cohort B2 with chemotherapy: Patients must be off myeloid growth factor for 
a minimum of 24 hrs. 
2.  Platelet count:  
a. For Cohorts A1, A2, B1 and B2 (with omission of chemotherapy): ≥ 50,000/µl, 
transfusion independent as defined by 5 days with no platelet transfusion  
b. For Cohort B2 (with chemotherapy): ≥ 75,000/µl, transfusion independent as 
defined by 5 days with no platelet transfusion  
3. QTc Interval: ≤ 500 ms (Grade 2) (Applicable if an ECG required at end of course) 
 
 
If criteria to begin subsequent course of therapy are not met for > 28 days, then patient will be 
removed from protocol therapy.  
 
4.5 
Concomitant Therapy 
 
4.5.1 
No other cancer chemotherapy or immunomodulating agents will be used.   
 
4.5.2 
Palliative radiotherapy is not allowed on study.   
 
4.5.3 
Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general supportive care 
are to be used as necessary (see Section 5.0). 
 
 
4.5.4 
Patients may not receive pharmacologic doses of corticosteroids above that needed for physiologic 
replacement EXCEPT as needed to manage allergic/infusion reactions or to prevent transfusion 
reactions.  Inhaled corticosteroids are allowed.   
 
4.5.5  
The in vitro studies have demonstrated that CYP3A, and UGT1A4 are primarily involved in the 
metabolism of lorlatinib, with additional minor contributions from CYP2C19 and CYP2C8. Inhibition 
or induction of the above enzymes may result in potential alteration of lorlatinib systemic exposure.  
 
Coadministration of 200 mg daily doses of itraconazole (a strong CYP3A4/5 inhibitor) with a single 
100 mg of lorlatinib increased lorlatinib AUCinf by 42% and Cmax by 24%. Coadministration of 600 
mg daily doses of rifampin (a strong CYP3A4/5 inducer) with a single 100 mg dose of lorlatinib 
decreased lorlatinib AUCinf by 85% and Cmax by 76%. Concomitant administration of lorlatinib 
and rifampin led to elevated AST and ALT levels in all subjects. Thus, use of strong CYP3A4/5 
inducers with lorlatinib is contraindicated. 
 
In the lorlatinib clinical DDI studies, at steady state, lorlatinib induced CYP3A and P-gp to moderate 
extent and CYP2B6 and CYP2C9 and UGT to a weak extent . 
 
Thus, to protect patient safety, the following action should be exercised 
 
1. Lorlatinib metabolism may be inhibited by strong CYP3A inhibitors leading to a potential 
increase in lorlatinib toxicities. Co-administration of strong CYP3A inhibitors (e.g., atazanavir, 
boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
troleandomycin, voriconazole, grapefruit juice or grapefruit/grapefruit-related citrus fruits [eg, 
Seville oranges, pomelos]) is not permitted at study entry and until the last lorlatinib dose. The 
use of these drugs during the study is not recommended and alternate medications should be 

 
 
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considered. If absolutely needed during the study, strong CYP3A inhibitors should be used with 
caution and patient closely monitored for safety.  
2. Use of strong CYP3A inducers with lorlatinib is contraindicated. Lorlatinib metabolism may be 
induced when taking strong CYP3A inducers (e.g., carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, St. John’s Wort) resulting in reduced plasma concentrations. Furthermore, 
when lorlatinib was coadministered with rifampin (Study B7461011), increases in AST and ALT 
were noted. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A 
inducer prior to initiating lorlatinib and until study treatment discontinuation.  
3. At steady state, lorlatinib induces CYP2C9 by a weak extent. Concurrent use of drugs that are 
CYP2C9 substrates with narrow therapeutic indices, such as warfarin, phenytoin or celecoxib, 
may have decreased effect.  Thus, concomitant CYP2C9 substrates should be used with 
caution. 
4. At steady state, lorlatinib induces CYP2B6 by a weak extent. Concurrent use of drugs that are 
CYP2B6 substrates, such as bupropion and efavirenz, may have less effect. Thus, 
concomittant CYP2B6 substrates should be used with caution.  
5. Lorlatinib induces CYP3A which may lead to a decreased effect of concurrently used CYP3A 
substrates (eg. hormonal contraceptives etc.). Co-administration of lorlatinib with CYP3A 
substrates with a narrow therapeturic index (NTI) such as alfentanil, fentanyl (including 
transdermal patch), astemizole*, cisapride*, cyclosporine, dihydroergotamine, ergotamine, 
pimozide, quinidine, sirolimus, tacrolimus, terfenadine* (*withdrawn from US market) is not 
permitted at study entry and until 12 days after the last lorlatinib dose. However if it is absolutely 
necessary to use, sponsor approval is required and the dose of the CYP3A substrate may need 
to be increased. The NTI CYP3A substrate should be started only after at least 14 days of 
continuous lorlatinib dosing. If there is a change in the lorlatinib dosing regimen such as a 
dosing interruption or dose reduction, the administration of the NTI CYP3A substrate should 
be stopped and resumed at a readjusted dose only after at least 14 days of resumed lorlatinib 
dosing. 
6. At steady state, lorlatinib induces P-gp by a moderate extent. Concurrent use of drugs which 
are P-gp substrates with a narrow therapeutic index may have decreased effect. The 
concurrent use of drugs which are P-gp substrates with narrow therapeutic index, such as 
digoxin is not permitted at study entry. The use of these drugs during the study is not 
recommended and alternate medications should be considered. If absolutely necessary to use 
during the study,it should be initiated following sponsor approval, and be used with caution.  
7. The Sponsor can be contacted with questions regarding concomitant use of specific drugs. 
 
4.5.6 
Hormonal Contraception 
Females of childbearing potential should be advised to avoid becoming pregnant while receiving 
lorlatinib. A highly effective nonhormonal method of contraception is required for female patients 
during treatment with lorlatinib because lorlatinib can render hormonal contraceptives ineffective. 
If a hormonal method of contraception is unavoidable, then a condom must be used in combination 
with the hormonal method. Effective contraception must be continued for at least 21 days after 
completing therapy. During treatment with lorlatinib and for at least 97 days after the final dose, 
male patients with female partners of reproductive potential must agree to use effective 
contraception, including a condom, and male patients with pregnant partners must agree to use 
condoms.   
 
 
 

 
 
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5.0 SUPPORTIVE CARE 
 
5.1   
Prophylaxis for Pneumocystis Jiroveci Pneumonia (PJP) 
All patients should receive PJP prophylaxis according to institutional guidelines. Bactrim 
(sulfamethoxazole and trimethoprim) Trimethoprim is a substrate for CYP2C8/9 and CYP3A4. It 
also is a moderate inhibitor of CYP2C8/9. Lorlatinib is metabolized by CYP3A4/5, CYP2C8, 
CYP2C19 and UGT1A4. It is also an inhibitor and inducer of CYP3A4 with the net effect being 
induction. It also inhibits CYP2C9. And it induces CYP2B6. 
  
Effect of lorlatinib on Bactrim: Because lorlatinib is an inhibitor of CYP2C9, it could increase 
trimethoprim concentrations. At the same time, lorlatinib also has a net induction effect on CYP3A4 
which could decrease trimethoprim concentrations. The overall effect is hard to predict. 
  
Effect of Bactrim on lorlatinib: since trimethoprim is an inhibitor of CYP2C9 it could increase 
lorlatinib concentrations. 
  
Hence, overall the use of Bactrim is permitted but the site/investigator should do so with caution, 
being aware of the possibility of increased lorlatinib concentrations and difficulty to predict change 
in trimethoprim concentrations. Alternative PJP prophylaxis medications such as pentamidine are 
acceptable without caution.  
 
5.2  
Use of Myeloid Growth Factors  
Myeloid growth factors are allowed on cohort B2, concomitant chemotherapy arm when 
chemotherapy is being administered. In all other cohorts, myeloid growth factors are only to be 
utilized in the setting of Grade 3 or 4 neutropenia together with documented invasive fungal 
infection, bacteremia, or fever with sepsis physiology.  The study chair should be notified in the 
event of myeloid growth factor use.  Patients who receive myeloid growth factor for Grade 3 
neutropenia will not be evaluable for dose-limiting neutropenia in that course.  
 
5.3   
Antiemetic  
Lorlatinib is not anticipated to be emetogenic.  For patients who develop nausea in any cohort, 
appropriate non-corticosteroid antiemetics should be utilized according to institutional guidelines.   
 
5.4 
For Supportive Care of Toxicities Attributable to Protocol Treatment, please see Section 
4.3.3 
 
  
 
 

 
 
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6.0 
DRUG INFORMATION 
 
6.1 
Lorlatinib (PF-06463922) 
 
Structure and molecular weight:  
Name: Lorlatinib (PF-06463922) acetic acid solvate.  
PF-0643922 and lorlatinib can be used interchangeably  
 
Molecular weight 466.46 Daltons (acetic acid solvate)  
 
Table 18. Toxicities:   
Information is based on observation of 476 patients with advanced ALK-positive or ROS1-positive 
non-small cell lung cancer who participated in study B7461001 (N=327) or Study B7461006 
(N=149) and received lorlatinib 100 mg once daily orally. 
The following side effects considered to be related to lorlatinib have been reported:  
Very Common  
(may affect 10 or more in 100 people) 
Common 
(may affect from 1 up to less than 10 in 100 
people) 
• 
Hypercholesterolemia  
• 
Hypertriglyceridemia  
• 
Mood effects  
• 
Cognitive effects  
• 
Peripheral neuropathy  
• 
Vision Disorder  
• 
Hypertension  
• 
Diarrhea  
• 
Constipation  
• 
Joint pain  
• 
Edema (especially peripheral)  
• 
Fatigue  
• 
Weight gain  
• 
Hyperglycemia  
• 
Hallucination and loss of contact with 
reality 
• 
Mental status changes  
• 
Speech effects  
• 
Pneumonitis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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The following events have also been reported in patients while they were taking lorlatinib, 
although there is not sufficient evidence that lorlatinib is related to them:  
 
Very common (may affect 10 or more in 100 people) 
• 
Liver enzyme elevation  
• 
Pancreative enzyme elevation  
• 
Anemia  
• 
Headache 
• 
Myalgia  
• 
Sleep effects  
• 
Rash 
 
Common (may affect from 1 up to less than 10 in 100 people) 
• 
Ejection fraction decreased  
• 
Syncope 
• 
Electrocardiogram changes (QT prologation)  
 
Uncommon (may affect less than 1 in 100 people) 
• 
Pancreatitis  
• 
Suicidal ideation 
• 
Psychosis  
 
Formulation and Stability: Lorlatinib will be provided in bottles containing 5 mg or 25 mg tablets 
(as the acetic acid solvate). Each bottle will contain 32 tablets. The 5mg bottle has a blue label and 
tablets are round with a white to off-white color. The 25mg bottle has a yellow label and tablets are 
hexagonal in shape with a white to off-white color. The film coated tablets contain lactose. 
 
Guidelines for Administration:  See also Treatment and Dose Modification in Section 4.0.  
Lorlatinib will be provided in bottles containing 5 mg or 25 mg tablets.  Each bottle will contain 
enough medication for 1 treatment course.  The bottles will be labeled with different color labels to 
differentiate between dosage strengths.  Site personnel must ensure that patients clearly 
understand the directions for self-medication.  Patients will be provided with patient diaries to record 
daily lorlatinib administration.   Patients must be instructed to record all doses including vomited or 
missed doses in the patient diaries. If doses are missed or vomited, this must be indicated in the 
source documents and CRFs. If a patient vomits within 20 minutes of dose administration, the 
patient should be re-dosed. If the patient vomits after the second dose, the patient should not be 
re-dosed again. If a patient vomits more than 20 minutes from dose administration, the patient 
should not be re-dosed and the next dose will occur at the next scheduled time.   
 
Lorlatinib will be dispensed at the beginning of each treatment course once criteria to initiate a 
treatment course have been met (Section 4.4) and in the absence of evidence of clinical or 
radiographic disease progression. If a patient meets criteria for an extended course, a bottle may 
be dispensed prior to day one of the next course. Drug reconciliation needs to be completed after 
each bottle administered and after each course per protocol in circumstances where the patient 
may not return to the pharmacy. Patients should be instructed to keep their medication in the bottles 
provided and not transfer it to any other container. Patients should be instructed to take lorlatinib 
at approximately the same time each day and not to take more than the prescribed dose at any 
time.  However, a variance of up to 12 hours is allowed for any given dose, rather than miss a day’s 
dose.  If a patient misses a daily dose, they must be instructed not to “make it up” the next day. If 
a patient inadvertently takes 1 extra dose during a day, the patient should not take the next dose 
of lorlatinib.    
 
 
 

 
 
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Whole Tablet Administration: Lorlatinib tablets should be taken with at least 8 oz. (240 mL) of 
water or enough water to fully swallow the tablet(s) if not able to take the full 8oz. Patients should 
be instructed to swallow the Lorlatinib tablets whole and not chew the tablet prior to swallowing.  
No Lorlatinib tablet should be ingested if it is broken, cracked or otherwise not intact. 
 
Dispersed Tablet Compounding and Administration (see instructions): If the subject is unable 
to swallow the tablets whole, they may be dispersed in a suitable liquid and administered as an oral 
dispersion. Instructions are included in the Investigational Product Manual, which describes the 
procedures for dispersing PF-06463922 5 mg and 25 mg tablets to deliver doses ranging from 10 
mg through 100 mg in oral dosing syringes. Changes to bioavailability between the whole and 
dispersed tablet are not expected.  Patients/caregivers who will be administering the oral dispersion 
will have mandatory, supervised, hands-on training at all NANT sites prior to performing the process 
at home. Additionally, written instructions for preparation and administration of lorlatinib oral 
dispersion will be given to patients/caregivers to take home.  
 
 
6.1.1 
Drug Supply and Accountability  
Lorlatinib will be supplied by Pfizer, Inc.  Lorlatinib will be shipped to treating institutions through 
the contract pharmacy, Almac. Instructions and forms for ordering lorlatinib from Almac are posted 
to the NANT website. 
 
Accountability for lorlatinib 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, use by each patient, and drug disposition/destruction 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 
Almac  Accountability records will include dates, quantities, batch/serial numbers, expiration dates 
(if applicable), and patient numbers. Upon confirmation that the last patient enrolled into the study 
has completed the treatment period, all unused, unopened, or expired lorlatinib should be 
maintained until notice from NANT Operations Center regarding destruction of drug or instructions 
regarding shipment to another facility.  These events will be performed in accordance with site 
pharmacy SOPs.  The site will maintain detailed records of the drug reconciliation and destruction 
with the study files. All material containing study drug will be treated as hazardous waste in 
accordance with governing regulations. 
 
6.2 
Topotecan  (SKF-104864, Hycamtin®) NSC #609699 (06/03/13)  
 
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 
topoisomeraseI-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%.  

 
 
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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 
60mL/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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Table 19. 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.  
 
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).   
Guidelines for Administration: See also Treatment and Dose Modification in Section 4.0.  
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.   
Supplier:  Commercially available. See package insert for further information.   
6.3 
Cyclophosphamide (Cytoxan) NSC #26271 (03/13/13)  
Source and Pharmacology: Cyclophosphamide is an alkylating agent related to nitrogen 
mustard. 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.  

 
 
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Table 20. 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 
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:  
Anytime 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.  
1Dependent on dose, age, gender, and degree of pubertal development at time of treatment  
2Risk increased with pulmonary chest irradiation and higher doses. (L) Toxicity may also occur 
later.  
 
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 25°C (77°F) is 
recommended. The product will withstand brief exposures to temperatures up to 30°C (86°F).  
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
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.   
Supplier: Commercially available from various manufacturers. See package insert for further 
information  
 
 
 
 
 
 
 
 

 
 
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6.4 Neulasta (PEG-FILGRASTIM)  
 
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) monomethoxypolyethylene 
glycol molecule to the N-terminal methionyl residue of filgrastim. The molecular weight of peg-
filgrastim 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 peg-filgrastim 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 post chemotherapy, 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. 
 
Unknown frequency and timing:  
Fetal toxicities and teratogenic effects of peg-filgrastim in humans are unknown. Conflicting data 
exist in animal studies. It is unknown whether the drug is excreted in breast milk. 
 
Supplier: Commercially available. See package insert for further information. 
 
Formulation and Stability: 
Supplied as a preservative-free solution containing 6 mg (0.6 mL) of peg-filgrastim (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 2 º-8ºC (36º-46ºF) and in the carton to protect from light. Prior to injection, peg-
filgrastim may be allowed to reach room temperature protected from light for a maximum of 
48 hours. Avoid freezing. 
 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol. 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. 
 
 
Table 21: PEG-Filgrastim Neulasta Toxicity: 
Likely 
(happens  to  21-100  
children out every 
100 children) 
Less Likely 
(happens  to  5-20  children  
out every 100 children) 
Rare 
(happens  to  <  5  children  out every 100 
children) 
• Mild to moderate 
medullary bone 
pain 
• 
Local pain or irritation at 
injection site 
• 
Headache 
• 
Increased alkaline 
phosphatase, lactate 
dehydrogenase and uric 
acid. 
• 
Thrombocytopenia 
• 
Low grade fever,  
• 
Allergic reactions (anaphylaxis, angioedema, 
or urticaria), generalized erythema and 
flushing 
• 
Splenomegaly, splenic rupture, sickle cell 
crises in patients with sickle cell disease 
(SCD) 
• 
 Excessive leukocytosis, Sweet's syndrome 
(acute febrile neutrophilic dermatosis) 
• 
Adult respiratory distress syndrome 

 
 
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6.5 
GRANULOCYTE COLONY STIMULATING FACTOR (G-CSF) (Filgrastim, Neupogen) 
 
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 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). 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 to 8 hours. 
 
Formulation and Stability:  
Supplied as a clear solution in 300 ug/ml (1 ± 0.6 x 108 U/mg) (1 ml or 1.6 ml) vials. Vials are 
preservative free and are intended to be single-use vials; do not reuse opened vials. Filgrastim 
must be stored between 2° and 8°C. Stability has been demonstrated for at least 24 months when 
stored under these conditions. Do not use if discolored or if there is particulate matter. For IV use, 
dilute in D5W to concentrations > 15 ug/ml; G-CSF is incompatible with normal saline. At dilutions 
from 5 ug/ml to 14 ug/ml, add human serum albumin to a final albumin concentration of 2 mg/ml to 
protect against absorption of the GCSF to container walls (glass or plastic). Filgrastim, when diluted 
as described above, is compatible with a number of plastics commonly used in the manufacture of 
syringes, IV bags, infusion sets, and IV pump cassettes. These include polyvinyl chloride, 
polyolefin, and polypropylene. Diluted Filgrastim should be stored at 2° to 8° C and used within 24 
hours. Do not shake or freeze.  
 
Supplier: Commercially available. See package insert for further information.  
 
Guidelines for Administration: See Treatment, Dose modifications and Supportive Care sections 
of the protocol. Administer once daily, subcutaneously without dilution or if necessary dilute with 
5% dextrose in water, preferably to concentrations of 15 ug/ml or greater for IV administration. 
Dilutions should be prepared as close to the time of administration as possible (up to 24 hours), 
since the product is preservative-free. When diluting Filgrastim to 5-14 ug/ml in D5W, it is necessary 
at all times to add human serum albumin, to reach a final albumin concentration of 2 mg/ml. 
 
 
 

 
 
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Table 22: Granulocyte colongy Simulating Factor (G-CSF) (Filgrastim, Neupogen) Toxicty  
Likely 
(happens  to  21-100  
children out every 100 
Less Likely 
(happens  to  5-20  
children  out every 100 
Rare 
(happens  to  <  5  children  out every 100 children) 
• 
Mild to moderate 
medullary bone 
pain 
• Local pain or 
irritation at 
injection site 
• Increased alkaline 
phosphatase, LDH 
and uric acid 
• Thrombocytopenia 
• Fever 
• Allergic reactions  (more common with IV than subcutaneous 
administration) 
• Skin rash, urticaria and/or facial edema 
• Respiratory wheezing and/or dyspnea 
• Hypotension and/or tachycardia 
• Low grade fever 
• Splenomegaly 
• Splenic rupture 
• Worsening of existing skin rashes 
• Sickle cell crises in patients with Sickle cell disease 
• Excessive leukocytosis 
• Cutaneous vasculitis 
• Adult respiratory distress syndrome 
• MDS or AML (in patients with severe chronic neutropenia and 
long term administration 
 

 
 
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7.0    
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
7.1 
Clinical and Laboratory Assessments 
All laboratory tests, physical exam including a neurological exam must be performed ≤ 14 days 
prior to study registration, except for β-HCG pregnancy test (if applicable) which must be done 
within 7 days of study registration. Baseline tumor disease evaluation (including appropriate 
imaging studies, bilateral bone marrow aspirate and biopsy for standard histology and urine 
catecholamines), EKG are required within 4 weeks prior to study registration and subsequent to 
any prior therapy. All patients regardless of marrow disease status at study registration are 
REQUIRED to have repeat bone marrow evaluations at each subsequent disease evaluation. 
Initiation of protocol therapy is required within 1 week of study registration. Neuropsychological 
evaluations and testing are part of the required observations; please see section 7.1.2.2 for details.  
Baseline neuropsychological testing for patients’ ≥ 3 years of age is to be performed after study 
registration and no later than day 1 of protocol treatment.  For patients’ < 3 years of age, a 
neuropsychological evaluation performed by a licensed psychologist is to be performed after study 
registration and no later than the end of the second week of therapy (Course 1 Day 14).  
 
OBTAIN OTHER ASSESSMENTS AS NEEDED FOR GOOD PATIENT CARE. 
 
Table 23. Required Observations 
Observation 
Baseline 
Course 1 
Course 2 
Courses 
3+ 
End of 
Therapy 
Physical Exam* 
(Ht, Wt, BSA, VS) + Neurological Exam1 
*Performance status required only at entry 
 
X 
Weekly 
Start of 
course 
Start of each course 
 
X 
CBC, Diff, Platelets1 
X 
A1, A2, B1: 
Weekly 
B2: Twice 
weekly  
A1, A2, B1: 
Start of 
course  
B2: Weekly 
Start of each course for 
A1, A2, B1 
Weekly for B2 
X 
AST, ALT, Alk Phos, Total + Direct 
Bilirubin, Albumin, Electrolytes, Calcium, 
Magnesium, Phosphorus, BUN, Serum 
Creatinine1 
X 
Weekly 
Start of 
course and 
once again 
in  Week 2 
or 3 
Start of each course 
X 
Serum Amylase and Lipase1 
X 
Weekly 
Start of 
course 
Start of each course 
X 
HDL, LDL, total cholesterol and 
triglycerides, glucose (Fasting preferred) 1 
X 
Every other 
week 
Start of 
course 
Start of each course 
X 
Hemoglobin A1C (HbA1c)  
X 
 
End of 
course  
With Disease 
Evaluations in Courses 
4 and 6 and after every 
4 Courses thereafter  
X 
Serum or urine -HCG1,2 
X 
 
Start of 
course 
Start of each course 
 
EKG (12-lead)3 
X 
 1 hour post 
day 1 dose 
End of 
course 
With Disease 
Evaluations in Courses 
4 and 6 and after every 
4 Courses thereafter  
X 

 
 
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Observation 
Baseline 
Course 1 
Course 2 
Courses 
3+ 
End of 
Therapy 
Plasma pharmacokinetic samples3 
(required for all patients) 
 
X 
See 
Section 8.1 
 
 
 
Neuropsychological assessments5 
X 
End of 
course 
End of 
course 
With Disease 
Evaluations in Courses 
4 and 6 and after every 
4 Courses thereafter  
X 
Bayley-III neuropsychological assessment 
for patients < 3 years of age only5 
X 
 
End of 
course 
End of course 6, 10 and 
then every 8 courses 
thereafter  
 
Collect, Review and Submit Patient 
Diaries 
 
X 
X 
X 
X 
Tests Obtained During Disease Evaluation Time Points 
Bilateral BM Aspirate + Biopsy for 
morphology6 
X 
 
X 
 
 
With Disease 
Evaluations in Courses 
4 and 6 and after every 
4 Courses thereafter 
X 
Anatomic imaging (CT or MRI scan) of 
chest/abdomen/pelvis plus any other 
known sites of measurable disease 4, 6 
X 
 
X 
X 
MIBG diagnostic scan4, 6 
(Use same isotope with each scan)  
X 
 
X 
X 
Blood and Bone Marrow for N04-05 
X 
 
With 
Disease 
Evaluation6 
X 
Blood for circulating tumor DNA (ctDNA) 
profiling7 (optional) 
X 
 
With 
Disease 
Evaluation6 
X 
Archival tumor tissue submission 
(optional) 
 
X 
See 
Section 8.3 
 
 
 
Bone Marrow aspiration for Optional 
Correlative Study  
X 
 
With 
Disease 
Evaluation6 
With Disease 
Evaluations in Courses 
4 and 6 and after every 
4 Courses thereafter 
 
1. 
Physical exams and laboratory assessments timed for the start of a course may be obtained within 96 hours prior to day 1 of 
each subsequent course of protocol therapy. For cholesterol and triglycerides, 8 hour fasting level preferred; if non-fasting and 
elevated needs to be repeated in fasted state preferrably within 72 hours.  
2. 
Obtain for females 10 years of age and older or post-pubertal. 
3. 
EKGs should be performed ≤ 4 weeks prior to study enrollment, Day 1 1 hour post-dose, and on day 22 – day 28 of course 2, 
4, 6 and every 4th course thereafter and at the end of treatment. When EKG and PK sample collection coincide, the PK will take 
priority so that it is collected at nominal time point and the EKG can be collected after the PK is collected.  
4. 
Tumor imaging = CT and/or MRI (Chest abdomen pelvis) plus CT/MRI Imaging of any other sites with MIBG uptake for optimum 
visualization of all areas of bulk tumor (primary & metastasis). If patient has a history of tumor lesions in the skull, orbits or brain, 
OR if MIBG scan shows uptake in these same areas, then a CT or MRI of the brain/orbits is strongly suggested.  For patients 
with epidural or hepatic tumor lesions, MRI is the recommended imaging technique. 123I-MIBG scans are preferred.  Omit for 

 
 
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patients known to be MIBG non-avid and replace with 18FDG-PET (preferred) or bone scan. FDG-PET is required if used at 
baseline to document evaluable tumor lesion(s) for response. All patients are required have a diagnostic bone marrow sent with 
each disease evaluation.  
5. 
For patients < 3 years old, a neuropsychological evaluation (Bayley-III testing) will be performed by a licensed psychologist 
after study registration but no later than the end of the second week of therapy (day 14 of course). Bayley-III will only be done 
at baseline, end of course 2, 6, 10 and then every 8 courses thereafter for duration of treatment (+/- 5 days). However, parent 
questionnaires for patients < 3 years of age will be done at the same time points as for patients’ ≥ 3 years of age. More frequent 
neuropsychological monitoring may be needed if results identify risk of cognitive or behavioral decline (see Section 4.3, Table 
16a and section 7.1.2.3 for assessment schedule details). Final testing will occur at end of treatment with the exception of 
Bayley-III.  
6. 
All disease status tests must be performed ≤ 4 weeks prior to study enrollment and on week 4 (day 22-28) of courses 2, 4, and 
6, and after every 4 courses thereafter (i.e. day 22-28 of course 10, 14, etc.). Any course can be delayed by up to 4 days due 
to scheduling conflict or delays only if the prescribed bottles for that given course have sufficient tablets (32 tablets/bottle) to 
allow for course extension. 
7.    Blood Specimens for Circulating Nucleic Acid (CNA) Profiling: blood specimen optimized for plasma preparation for nucleic acid 
analysis (e.g., circulating tumor DNA (ctDNA) or RNA (cfRNA)) will be collected at baseline and at every disease evaluation 
time point as well as end of therapy. 
7.1.2.  Neurologic assessments 
 
The information below is provided to augment and help grading of CTCAE criteria.    
 
7.1.2.1  Neurologic Examination  
A gross neurological exam will be performed by the oncologist prior to each course.   
 
7.1.2.2  Assessment of Neuropsychological Functioning 
Research investigating adult response to lorlatinib revealed dose limiting toxicity secondary to CNS 
effects. Specifically, mild to moderate cognitive symptoms including changes in speech, memory, 
and mood were observed. Such treatment related adverse events were noted to be generally 
intermittent and managed with dose hold or reduction. Therefore, it will be important to closely 
monitor neuropsychological functioning in children and young adults treated with this agent.  
 
Neuropsychological functioning will be routinely assessed via computerized and questionnaire 
screening instruments in order to measure potential changes in cognition, behavior, and mood 
associated with lorlatinib administration. Given the broad age range of patients enrolled on the 
study, effort was made to select measures that could assess the widest age range possible. As 
no single measure exists that covers infancy through adult years, separate test batteries were 
needed for children less than three years of age and those age three years and older.  
Adjustments were also made as necessary between certain age brackets based upon 
specifications of the measures. Batteries are comparable in domains assessed such that some 
analyses will be possible across batteries. Additionally, given the frequency in which 
neuropsychological monitoring must be conducted, measures were strategically selected so to 
minimize sensitivity to practice effects that can result from serial evaluation. The patient’s country 
of origin and primary language will be determined at the time of registration. Only measures with 
established language translations may be administered (See Appendix IV). Institutions will contact 
central site for specific test battery for non-United States English speaking patients. Any tests that 
do not have normative data from the patient’s country of origin will not be interpreted for clinical 
purposes. If neuropsychological questionnaires are not available in patient’s primary language, 
neuropsychological toxicity assessment will be based on the treating physician’s assessment.   
 
Neuropsychological Monitoring: Computerized measures (using iPads provided to sites by 
CogState) will be administered to patients at the time-points described in the Required 
Observations Table (Section 7.1) and Section 7.1.2.3 below. The computerized measure, Cogstate 
Research Battery, will be administered by qualified site personnel and will take approximately 10-
30 minutes to complete depending upon age of the patient. The CogState battery administered 
prior to course 1 will be performed twice to eliminate practice effects and then administered only 
once in subsequent courses. This measure is developed and validated by Cogstate. The specific 
age-based battery of test items (at time of testing) and descriptions are listed below, Table 24 and 
Section 7.1.2.4. Behavioral ratings questionnaires assessing health-related quality of life and 

 
 
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social, emotional, and behavioral functioning will also be completed by patients 18 years and older 
or by the parents of patients under 18 years of age.  
 
All neuropsychological monitoring measures will be interpreted by a pediatric neuropsychologist 
with extensive training in neuropsychological evaluation with medical populations. A baseline report 
will be provided to families if deficits or concerns are identified within 1 week of evaluation. 
Subsequent feedback will be provided only if a reportable event occurs and will be communicated 
to the family by the medical team in the context of their overall discussion of response to treatment 
and clinical decision making.  All study coordinators will have received specialized training in 
administration of pediatric measures and are familiar with limitations associated with children, 
adolescents, and young adults presenting with medical complications.  
 
Neuropsychological Evaluation for Children < 3 Years of Age: Given limited availability of 
performance based measures for young children, a more comprehensive evaluation of global 
functioning will be conducted periodically for children less than 3 years of age (See Section 7.1.2.3 
for schedule). It is likely that medical management and health status of the patient will in part guide 
feasibility and timing of assessments as it is important that patients are well enough to participate 
so as to ensure valid neuropsychological data. Neuropsychological function of children less than 
three years of age will be measured using a single comprehensive battery, the Bayley Scales of 
Infant and Toddler Development, Third Edition (Bayley-III; Section 7.1.2.4). Administration time is 
approximately 60-90 minutes. The Bayley-III must be administered and interpreted by a licensed 
psychologist. Institutions are encouraged to provide interpretive feedback to the patient and family, 
particularly if there is an issue of clinical concern. 
 
7.1.2.3  Neuropsychological Assessment Schedule and Reporting 
Neuropsychological monitoring for patients ≥ 3 years of age will be conducted at baseline, as 
defined by after study registration and no later than day 1 of course 1. Serial monitoring will be 
conducted on day 22-25 of course 1, course 2, 4, 6 and every 4th course thereafter.  Final screening 
will occur at end of treatment. Monitoring will coincide with disease evaluations and be in 
accordance with this standard required observation schedule unless toxicities observed require 
more frequent monitoring as detailed below. Cogstate will be administered twice in succession at 
baseline to allow for familiarization with the tasks and to eliminate practice effects. The second 
administration at baseline is recorded as true baseline performance data. Cogstate will be 
administered only once during all subsequent screening time points.  Behavioral measures are 
completed once at all time points. 
 
Central review of testing measures, including Cogstate testing and behavioral questionnaires, will 
be completed with notification of results within 72 hours (between days 26-28) via a 
neuropsychological status report (Appendix V). Reliable Change Index (RCI) scores will be 
generated for individual tests or scales for each visit to determine whether a clinically meaningful 
change in performance occurred relative to baseline or previous evaluations. The status report will 
indicate absence, risk, or presence of clinically significant decline. Risk for possible decline and 
modification of retest interval for neuropsychological monitoring will be determined utilizing a 25% 
impairment classification model in an effort to reduce the potential for type 1 error. Stated otherwise, 
increased screening to day 22-25 of every course is warranted when there exists evidence of 
significant change in performance in 25% of select administered measures. Meaningful change in 
performance is considered to occur when clinically significant decline is present in 50% of select 
administered measures. In such occurrences, the status report will note significant decline and 
corresponding severity grading criteria for consideration by the medical team as per study protocol. 
Plan for retest interval will be determined based upon decision by the medical team regarding 
dosing and in accordance with Section 4.3, Table 16a.  
 
Psychosis, as defined by confused thinking and altered sense of reality, has been reported as an 
adverse response in association with higher doses of lorlatinib administration. Neuropsychological 
evaluation within the context of this study cannot adequately assess for, screen, or address 
symptoms of psychosis. Given the necessary constraints of the technician administered, broad-

 
 
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based brief serial cognitive and behavioral assessment system utilized for the current study, 
screening of certain nervous system and psychiatric disorders will continue to be deferred to the 
medical team as part of the in person gross neurological exam. Special attention via qualitative 
review of behavioral rating measures will be given to item responses within the current 
neuropsychological screening and monitoring battery that suggest endorsement of potential 
atypical behaviors and, if present, will be included in the narrative of the neuropsychological status 
report for review by the medical team to further augment and help grading of CTCAE criteria by 
medical providers.  
 
Neuropsychological monitoring for patients < 3 years of age will also be conducted at baseline, as 
defined by after study registration but prior to Day 1 lorlatinib administration. Specifically, parent 
questionnaires for patients < 3 years of age will be completed according to the same observation 
schedule as for patients’ ≥ 3 years of age (baseline and day 22-25 of course 1, 2, 4, 6, and every 
4th course thereafter). Given the more lengthy administration time and required access to personnel 
with speciality professional licensure, the Bayley-III testing may be completed no later than the end 
of the second week of therapy (day 14 of course).  Repeat Bayley-III evaluation will occur at end of 
course 2, course 6, 10 and every 8 courses thereafter (±5 days) for the duration of protocol therapy. 
Institutions will not be required to conduct more comprehensive neuropsychological evaluations for 
individuals over 3 years of age; however, referral for more in-depth evaluation of cognitive skills is 
encouraged, particularly if there is an issue of clinical concern.  
 
Table 24. Serial Neuropsychological Monitoring 
Serial Neuropsychological Monitoring 
 
Child’s Age (Years: Months) 
Test 
<2:0 
2:0-
2:11 
3:0-
5:11 
6:0-
9:11 
10:0-
17:11 
≥18:0 
Cognitive Measures 
 
 
 
 
 
 
Global Cognitive Function and Development  
 
 
 
 
 
 
  Bayley-III 
X 
X 
 
 
 
 
  Detection (3 min) 
 
 
X 
X 
X 
X 
  Identification (3 min) 
 
 
X 
X 
X 
X 
  One Card Learning (6 min) 
 
 
 
X 
X 
X 
  One Back (4 min) 
 
 
 
X 
X 
X 
  Groton Maze Learning Test (7 min) 
 
 
 
X 
X 
X 
  International Shopping List (10 min) 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Behavioral Measures 
 
 
 
 
 
 
Behavioral/Social/Emotional Function 
 
 
 
 
 
 
ABAS-3 (15 min) c 
X 
X 
X 
X 
X 
Xa 
BASC-3 (15 min)d 
 
X 
X 
X 
X 
Xa 
BRIEF (10 min)e 
 
X 
X 
X 
X 
Xa 
PedsQL - Generic Version (5 min)f 
 
X 
X 
X 
X 
Xa 
PedsQL - Multidimensional Fatigue (5 min)f 
 
X 
X 
X 
X 
Xa 
PedsQL – Infant Scales (5 min) 
X 
 
 
 
 
 
Beck Depression Inventory-II (5 min) 
 
 
 
 
 
X 
Columbia Suicide Severity Rating Scale 
 
 
 
Xb 
Xb 
Xb 
a Patients ≥ 18 years of age will complete a self-report form. No parent report will be used for patients ≥18 
years. 
b Patients < 7 years of age do not complete. Patients 7-11 years of age will be provided with the C-SSRS 
Children’s Baseline and Since Last Visit Versions. Patients >12 years of age will be provided with the C-
SSRS Baseline and Since Last Visit Versions.  
c Version depending on age in years: ABAS-3 Parent/Caregiver Form Ages 0-5=0-5:11, Parent Form=6:0-
17:11, Adult Self-Report Form= ≥18  
d Version depending on age in years: BASC PRS-P =2:0-5:11, PRS-C = 6:0-11.11, PRS-A = 12:0-17:11, 
SRP-College = 18-25. 

 
 
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e Version depending on age in years: BRIEF-P=2-5:11, BRIEF=6-17:11, BRIEF-A= ≥18  
f Version depending on age in years: PedsQL Parent Report for Toddlers=2-4, Parent Report for Young 
Children=5-7, Parent Report for Children=8-12, Parent Report for Teens=13-18; Young Adult Report=18-
25, Adult Report= ≥26 
 
7.1.2.4 Description of Neuropsychological Computerized Screening Measures 
 
Detection (Psychomotor Function) 
The Detection task is a measure of psychomotor function and uses a well-validated simple reaction 
time paradigm with playing card stimuli.  In this task, the playing cards all depict the same joker. 
The patient is asked to press the “Yes” key as soon as the card in the center of the screen turns 
face up. The software measures the speed and accuracy of each response. 
 
Identification (Attention) 
The Identification task is a measure of visual attention and uses a well-validated choice reaction 
time paradigm with playing card stimuli.  In this task, the playing cards are all either red or black 
jokers. The patient is asked whether the card displayed in the center of the screen is red. The 
patient responds by pressing the “Yes” key when the joker card is red and “No” when it is black. 
The software measures the speed and accuracy of each response. 
 
One Card Learning Test 
The One Card Learning Test uses a pattern separation paradigm to measure visual memory. In 
this test, a playing card appears in the center of the screen. The patient must immediately indicate 
whether or not the same card has been presented before in this task by selecting the “Yes” button 
or “No” key. If an incorrect response is given an error noise is heard. Only a few of the cards will 
repeat during the task. Patients must work as quickly and as accurately as they can. The 
proportion of total correct responses is recorded to assess accuracy of performance. 
 
One Back (Working Memory) 
The One Back task is a measure of working memory and uses a well-validated n-back paradigm 
with playing card stimuli.  In this task, the playing cards are identical to those found in a standard 
deck of 52 playing cards (without the joker cards). The patient is asked whether the card displayed 
in the center of the screen is the same as the card presented immediately previously.  The patient 
responds by pressing the “Yes” or “No” key. The software measures the speed and accuracy of 
each response. 
 
The Groton Maze Learning Test (Executive Function) 
The Groton Maze Learning Test is a measure of executive function using a maze learning 
paradigm. The subject is shown a grid of tiles on a computer touch screen. A pathway is hidden 
among these locations. The patient is instructed to start at the top left blue tile and then move 
one tile at a time toward the end (bottom right) while adhering to specific task rules. The task 
utilizes a trial and error feedback approach in which after each move the computer indicates 
whether this is correct or incorrect move. Once completed, the test is repeated approximately 4 
times. The software records total number of errors across five consecutive trials.   
 
The International Shopping List Task (Verbal Learning) 
The International Shopping List task is a measure of verbal learning and uses a well-validated list-
learning paradigm. A list of high frequency, high imagery, concrete nouns (items from a shopping 
list) are read to the patient by the qualified site personnel at the rate of one word every 2 seconds. 
Once all 12 words have been read, the patient is asked to recall as many of the words as he/she 
can.  As the patient recalls each word, the qualified site personnel uses the mouse or stylus to 
select the appropriate button on the computer screen. When the patient cannot recall any more 
items, the entire word list is read a second time in the same order. The qualified site personnel 
records the words recalled by the patient on this trial. This process is then repeated a third time. 
The software measures the number of correct responses as recorded by the qualified site 
personnel. 

 
 
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International Shopping List Test – Delayed Recall (Verbal Memory) 
The delayed recall condition requires the patient to recall the words from the list 10-30 minutes 
later without having the list read again.  The qualified site personnel records all words recalled by 
selecting the corresponding button on the screen. The software measures the number of correct 
responses. 
 
7.1.2.5  Description of Objective Neuropsychological Evaluation Measures (administered by licensed  
psychologist) 
 
Intelligence/Global Measures of Functioning 
 
Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) 
The Bayley-III assesses a wide range of functioning, including cognition, language, motor, social-
emotional, and adaptive development. Cognition, language, and motor function are assessed via 
child interaction through tasks and activities administered by a qualified examiner. Social-emotional 
and adaptive behavior are measured via parent questionnaire. The measure is a well-standardized 
instrument (normative sample size of 1,700 stratified by age) commonly used to assess 
development and cognitive functioning in infants. Reliability is adequate, as evidenced by the 
internal consistency of the cognitive (.87), gross motor (.91), and fine motor (.86) scales. The 
validity of this measure can be found through its correlations with other well validated measures of 
infant development (e.g., the Bayley-II, the Preschool Language Scale-4), Peabody Development 
Motor Scales-2, and Adaptive Behavioral Assessment System-II). Additionally, scores on this 
measure have been shown to reliably differentiate among groups of children with clinical and 
medical conditions including Down syndrome, cerebral palsy, prematurity, and pervasive 
developmental disorders.  
 
7.1.2.6  Parent or Self-Report Questionnaires 
 
Adaptive Behavior Assessment System – 3rd Edition (ABAS-3)  
The parent-report and self-report forms from the ABAS-3 will be used for the assessment of 
adaptive skills for individuals across all ages. Separate scaled scores are available for 9-11 areas 
of functioning dependent upon age. Internal consistency has been reported to be 0.96 or greater 
for the composite adaptive behavior scale and between 0.86 and 0.99 for the sub-scales. Construct, 
convergent, and discriminant validity have also been established for this measure.  
 
The Behavior Assessment System for Children, Third Edition (BASC-3) 
The BASC-3 is a questionnaire assessing behavioral, emotional, and adaptive functioning across 
home, school, and community settings. There are several forms based on age and respondent role. 
For purposes of this study, the Parent Rating Scales (PRS) will be used for ages 2-5 (Preschool 
form, PRS-P), 6-11 (Child form, PRS-C), 12-17 (Adolescent form, PRS-A).  The Self-Report of 
Personality (SRP) College Form will be used for ages 18-25. The form generally contains 9 clinical 
scales and 5 adaptive indices. The clinical scale includes the externalizing problems, internalizing 
problems, and behavioral symptom indices. Adaptive scales include overall adaptive skills, 
including functional communication, activities of daily living, social and leadership skills, and 
adaptability. The reliability of the BASC-3 is strong with internal consistency averaging above .80 
for all the age-specific versions of this questionnaire (preschool, child, adolescent) and average 
test-retest reliability is .86.  This measure correlates strongly with other well-validated broad band 
child behavioral checklists such as the Child Behavior Checklist (CBCL). Note: General combined 
sex norms should be used when scoring the BASC-3. 
 
The Behavior Rating Inventory of Executive Function (BRIEF) 
The BRIEF is a questionnaire designed to assess behavioral manifestations of executive 
functioning and includes multiple versions. Parents of participants ages 2-5 years will complete the 
63-item preschool version (BRIEF-P). Parents of participants ages 6-17 years will complete the 
BRIEF Parent Form, which consists of 86 individual items from which eight clinical scales, two 

 
 
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indices, and one composite score are derived. Patients who are ≥18 years of age will complete a 
75-item self-report adult version (BRIEF-A). Scores are standardized by age and gender. High 
internal consistency (.73-.98) and test-re-test reliability (.76-.90). Construct, content, convergent, 
and discriminant validity have been established. 
Pediatric Quality of Life Inventory Version 4 (PedsQL 4.0) – General Core Scales 
The PedsQL 4.0 is a modular approach to measuring health-related quality of life in healthy children 
and adolescents as well as those with acute and chronic health conditions. The Generic Version 
consists of 23 items, with separate parent-report forms for ages 2-4, 5-7, 8-12, and 13-18. Patients 
who are 18-25 and ≥26 years of age will complete the Young Adult Report and Adult Report (self-
report) forms, respectively. The questionnaire yields domain scores for Physical, Emotional, Social, 
and School Functioning as well as summary scores for Total Quality of Life, Physical Health, and 
Psychosocial Health. Reliability and validity have been established for this measure.  
 
Pediatric Quality of Life Multidimensional Fatigue Scale 
The PedsQL Multidimensional Fatigue Scale is an 18-item questionnaire comprised of three 
subscales: general fatigue, sleep and rest fatigue, and cognitive fatigue. The parent version can be 
completed for children ages 2-18, with separate parent-report forms for ages 2-4, 5-7, 8-12, and 
13-18. Patients who are 18-25 and ≥26 years of age will complete the Young Adult Report and 
Adult Report (self-report) forms, respectively. Reliability and validity have been established for this 
measure. Research has demonstrated that scores on the fatigue scale significantly differentiated 
between patient samples and healthy controls. 
 
Pediatric Quality of Life Infant Scales 
The PedsQL Infant Scales were designed as a generic parent report measure of health-related 
quality of life for healthy and ill infants ages 1-24 months. It is composed of 36 items for infants 
ages 1-12 months and 45 items for infants ages 13-24 months comprising 5 dimensions: physical 
functioning, physical symptoms, emotional functioning, social functioning, and cognitive 
functioning. Research demonstrated excellent internal consistency reliability for the Total Scale 
Scores (.92), strong construct validity, and distinguished between healthy controls and patient 
samples. 
 
Beck Depression Inventory - Second Edition (BDI-II) 
The BDI-II is a 21-item, self-report rating inventory that measures characteristics of attitudes and 
symptoms of depression, including scale items capturing mood, suicidal ideation, somatic 
complaints (appetite, sleep, fatigue), and cognitive symptoms (punitive thoughts, poor 
concentration, self-criticism). Requires a fifth to sixth grade reading level to adequately understand 
questions. Internal consistency ranges from .84 to .93. Over short intervals, test-retest correlations 
are adequate (.74-.75) to strong (.93-.96). Research demonstrates strong construct validity.  
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a simple and short method of assessing both behavior and ideation that tracks 
all suicidal events and provides a summary of suicidality.  It assesses the lethality of attempts and 
other features of ideation (frequency, duration, controllability, reasons for ideation and deterrents), 
all of which are significantly predictive of completed suicide. Research demonstrated good 
convergent and divergent validity and high sensitivity and specificity.  It has been validated for use 
in individuals age 12 years and older. The children’s version is an un-validated measure developed 
for use in pediatric populations ages 7-11 years. 
 
7.2 
Recommended Follow-Up Observations 
 
 
The following are recommendations only, but may be altered at discretion of treating physician.   
 
Repeat the following if abnormal on a monthly basis until stable or normalized after the end of  
 
therapy. If normal at the end of therapy then repeat only as clinically indicated:  
 
 
 

 
 
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1. History, physical exam (Ht, Wt, VS) 
2. CBC/Differential, Platelets, AST, ALT, Bilirubin, BUN, Creatinine HDL, LDL, total cholesterol and 
triglycerides 
 
Patients will be followed for life for any delayed toxicities related to protocol therapy and for the 
development of second malignancies.  
 
After completion of protocol therapy, the disease status, sites of relapse, and last alive date will be 
recorded until first relapse/progression, after which only last alive date will be reported, as well as 
date of death and cause of death (if applicable).  
 
7.3 
Documentation of Tumor Response 
 
Disease evaluation will take place on or after Week 4 of courses 2, 4, and 6, and after every 4 
courses thereafter (i.e. after day 1 of week 4 of courses 10, 14 …).  It is recommended that all 
scans and tests previously done to document disease status be performed in subsequent 
evaluations of disease status (see Section 7.1).  
 
All patients are required to have a bilateral diagnostic bone marrow aspirate and biopsy done with 
each disease evaluation.  
 
Once a patient receives therapy other than prescribed on this protocol, no further scans or bone 
marrow evaluations will be required for this protocol since the patient will no longer be evaluable 
for response to protocol therapy. 
 

 
 
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8.0 
PHARMACOKINETIC AND BIOLOGY STUDIES  
 
Collection of plasma samples for lorlatinib pharmacokinetic studies is required during course 1 for all 
patients during both the dose escalation and expansion cohort phases of the study. In addition, 
samples are required for evaluation of minimal residual disease via NB5 assay by TLDA.  
 
Collection of other samples for correlative biology studies is optional and not required for 
study entry. Although these studies cannot be mandated, all institutions are strongly urged 
to submit specimens for all consenting patients.  
 
Table 25 summarizes pharmacokinetic samples to be collected during course 1. Please see Appendix 
II for a detailed summary of blood draws that also includes samples for correlative studies. For 
patients with a weight below the minimum required to tolerate all blood draws requested for correlative 
studies, please consult with study chair to determine prioritization of samples.   
 
8.1  
Lorlatinib Pharmacokinetics (PK) (Required) 
 
8.1.1 
Sample Schedule 
All efforts will be made to obtain the pharmacokinetic samples at the exact nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (e.g., within 6 minutes of a 
60 minute sample) from dosing will not be captured as a protocol deviation, as long as the exact 
time of the sample collection is noted on the source document and case report form (e.g., Medidata 
Rave). 
 
Samples will be collected at the following time points for the first treatment course: 
 
Table 25. PK Sample Collection Schedule  
 
 
 
 
 
 
 
 
 
 
 
 
*Day 15 PK sampling can be performed within a +/- 2 day window. Please contact NANT Operations 
Center to discuss if you cannot abide by this schedule.  
 
8.1.2 
Plasma PK Sample Collection Procedure and Processing Instructions 
 
NOTE: Lorlatinib is light sensitive; all steps must be performed out of direct light! It should 
be noted that once collected, samples should be processed immediately and kept out of direct light 
due to the light sensitive nature of lorlatinib. Once frozen, samples must not thaw, including during 
shipment. If sample(s) are inadvertently thawed, please notify the NANT Operations Center so the 
results can be appropriately tagged and if shipped, should be included in the transmittal form. 
 
TIME FROM BLOOD COLLECTION TO FREEZING OF PLASMA MUST NOT EXCEED 45 MINUTES 
 
 
1. Collect 3 mL whole blood into a K2EDTA (lavender top) tube at specified time points. 
2. After collection, gently invert sample 15 times to completely mix whole blood and 
anticoagulant. 
Sample 
# 
Cours
e 
Day 
PK Sample Time Point 
(hours) 
Amount of Blood 
Needed 
1 
1 
1 
Pre-dose 
3.0 mL 
2 
1 
1 
1 hr 
3.0 mL 
3 
1 
1 
2 hr 
3.0 mL 
4 
1 
2 
24 hr (pre-2nd dose) 
3.0 mL 
5 
1 
15* 
Pre-dose 
3.0 mL 
6 
1 hr 
3.0 mL 
7 
2 hr 
3.0 mL 
8 
4 hr 
3.0 mL 
9 
6 hr 
3.0 mL 

 
 
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3. Blood sample should then be immediately placed into an ice bath to be kept at 2°C - 8°C 
during the harvesting of plasma. 
4. Whole blood samples should be centrifuged at 4°C for 10 min at 1,700 x g to separate the 
plasma from the blood cells. 
5. Transfer plasma using a clean pipette; split each sample into 2 2mL AMBER cryovial aliquot 
tubes, each aliquot containing approximate 0.75 mL plasma. 
6. Store plasma samples immediately in a -20°C freezer. Excursions +/- 10°C are permitted. 
7. Samples must be shipped frozen on dry ice. Sufficient dry ice should be used to ensure that 
samples remain frozen for at least 72 hours. 
 
The PK samples must be processed and shipped as indicated to maintain sample integrity.  Any 
deviations from the PK processing steps, including any actions taken, must be documented and 
reported to the NANT Operations Center.  On a case-by-case basis, the sponsor may make a 
determination as to whether sample integrity has been compromised.  Any sample deemed outside 
of established stability, or of questionable integrity, will be considered a protocol deviation. 
 
8.1.3  
Sample Labeling Instructions 
PK samples will be labeled with pre-filled labels provided by Covance. It will include NANT ID #, 
Protocol # N15-02, collection date, time point (including course and day such as, C2D2) as well as 
the nominal time point of the sample (such as pre-dose, 1hr, 2hr, etc.). Please ensure the samples 
are de-identified and contain no protected health information (PHI).  
 
8.1.4   Shipment of Pharmacokinetic Samples 
 
All primary PK plasma samples should be batched at the end of Course 1 and shipped to: 
 
For US and Canada site(s) 
Covance Central Laboratory Services, Inc. 
8211 SciCor Drive 
Indianapolis, IN 46214-2985 
Phone: 317-271-1200 
Fax: 317-273-4030 
 
For EU site(s) 
Covance Central Laboratory Services SA 
Rue Moise-Marcinhes 7 
1217 Meyrin, Geneva Switzerland 
Phone: +41-58-989-7000 
Fax: +41-58-989-1999 
 
 
NOTE; Lorlatinib back up PK plasma samples should be stored on site as per protocol and  
batch shipped at a later time upon request.  
 
8.1.5     Methodology  
1. Lorlatinib plasma samples will be analyzed using a validated analytical method in compliance 
with Pfizer standard operating procedures. 
2. Plasma concentrations of lorlatinib and other possible metabolites of lorlatinib may be 
determined using validated or non-validated methods. 
 
8.2 
Correlative Pharmacodynamics Studies from peripheral blood (Optional) 
 
8.2.1 
Sampling Strategy for Plasma Collection for cell-free ctDNA Analyses 
The purpose of this optional correlative study is to prospectively and serially assay the blood of 
children treated with lorlatinib on this trial for cell-free circulating tumor DNA (ctDNA). We will 
perform these studies using Foundation Medicine’s cell-free DNA technology. Peripheral blood 

 
 
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samples will be obtained at study entry and at each anti-tumor evaluation time point.  The vast 
majority of peripheral blood draws will be obtained through a central venous line (CVL). Older 
subjects may elect routine venipuncture, but blood for this study will be drawn at a time when blood 
is being obtained for standard-of-care evaluations (typically with a CBC, see Table 23 for time 
points). For logistical purposes, it is preferable to obtain and ship these specimens on a Monday – 
Thursday schedule. Please complete a specimen transmittal form to be sent to NANT Operations 
Center at the time of shipment. Whole blood samples will be collected in one Streck Cell-Free DNA 
BCT tube (8.5 mL).  
 
All samples passing laboratory criteria will be tested. At the time of testing, laboratory personnel at 
Foundation Medicine will prepare DNA from plasma samples, perform DNA sequencing of the 
panel of genes, and analyze the results per approved and pre-specified internal laboratory 
protocols.  
 
The results are for research use only and will not be used for clinical management. No research 
data will be disclosed to participating subjects, families or clinicians not part of the study team. 
 
8.2.2 
Sample Handling Instructions 
 
At time of enrollment, please contact NANT operations to request FoundationACT kits. 
1. Step #1: Check special tube provided in FoundationACT kits to confirm liquid is clear and 
without cloudiness or crystals  
2. Step #2: Label tube with instructions specified in section 8.2.3 below. 
3. Step #3: Collect two tubes of whole blood (8.5mL/tube) 
o Prevent backflow: tube contains chemical additives and it is important to avoid 
backflow into patient  
o 
Fill tube completely (8.5mL/tube) 
4. Step #4: Remove the tube from adapter and immediately mix by gentle inversion 8 to 10 
times. Inadequate or delayed mixing may result in inaccurate test results. One inversion is a 
complete turn of the wrist, 180°, and back.  
5. Step #5: Place specimens, completed requisition form and NANT transmittal form found on the 
NANT 15-02 protocol page of the NANT website onto the FoundationACT specimen collection 
kit.  
6. Step #6: Preferably, on the same day of collection ship via FedEx overnight delivery at ambient 
temperature. Do not freeze or refrigerate blood samples. Keep at 43-99° F (6-37°C).  
 
8.2.3 
Sample Labeling Instructions 
Please ensure that each sample has an appropriate adhesive label printed and affixed to each tube 
with the following information: Patient Study  ID #, Protocol # N15-02, Time point (including course 
and day such as, C2D28), and the date of the blood draw. No other identifiers should be included 
on the label. 
 
8.2.4 
Sample Shipment 
 
Accessioning, Clinical Laboratory  
Foundation Medicine, Inc. 
150 Second Street, Cambridge, MA 02141 
 
Phone: 888-988-3639 
 
8.3 
Correlative Biology Studies from Tumor Tissue and Bone Marrow (Optional) 
 
The purpose of this optional correlative study is to decipher whether actionable driver mutations in 
ALK are found in all or a subset of tumor cells, and to compare diagnostic and relapse tissue when 
available. Additionally, we will define pre-existing and emerging sub-clonal and clonal driver 
mutations throughout the ALK-RAS-MAPK pathway using a neuroblastoma-specific ultra-deep 
sequencing platform to assay for sub-clonal mutations of all tumors (preferably pairs) obtained on 
this study. Samples will be evaluated for exploratory analyses to predominantly define the clonal 

 
 
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evolution of relapsed neuroblastoma genomes by comparing matched tumor samples (diagnosis 
and/or recurrence) for detection of mutations, copy number alterations and translocations.  
 
Tumor tissue will be requested for all research subjects who consent to this part of the study from 
all time points. The optimal and most important sample will be tumor at the time of study enrollment, 
but tumor tissue from diagnosis or at any other time point during therapy prior to treatment with 
lorlatinib will be accepted. This can be archived tissue (frozen or paraffin) from the primary 
institution. If a tumor block is not available, then 15 unstained slides (4-6uM in thickness) of tissue 
cut from the block may be shipped instead.  
 
Bone marrow aspirates: 4mL obtained bilaterally from each iliac crest (right and left) placed in 
separate green top (heparinized) tubes to be sent at room temperature to Mosse Laboratory.  
Aspirate specimens are collected at the same time the patient is undergoing baseline and 
subsequent disease evaluations on treatment and end of therapy.   These specimens are to be 
collected Monday – Thursday ONLY and must be shipped the same day as the procedure is 
performed using Federal Express overnight priority delivery.  These samples must be received 
within 24 hours of obtaining the sample.  No Friday shipments are allowed. Archival samples should 
be shipped during Course 1 of protocol therapy and no later than Course 2.   
 
Tumor tissue and bone marrow aspirate specimens should be sent to: 
 
Yael P. Mosse, MD 
The Children’s Hospital of Philadelphia 
The Colket Translational Research Building 
Room 3300 
3501 Civic Center Blvd 
CTRB 9006 
Philadelphia, PA 19104 
Office: 215-590-0965  
Fax: 267-426-0685 
 
8.3.1 
Sampling Strategy 
All specimens must be labeled with the patient’s NANT ID number, specimen type (primary or 
metastatic, bone marrow R and L), collection date and timing: for tumor tissue label with diagnosis, 
second look surgery, first relapse, subsequent relapse sample, for bone marrow: label with 
treatment course number.   Submit with NANT specimen transmittal form. 
 
8.4 
Evaluation of Minimal Residual Disease by NB5 Assay  
 
Patients will be required to co-enroll onto the NANT Biology Study to support assessment of 
minimal residual disease (MRD) by NB5 assay. We will employ the NB5 assay on blood or bone 
marrow obtained from patients on study. This assay is a well-developed assay for the quantification 
of MRD within the NANT consortia. It will be performed at CHLA. It is a 5-gene RT PCR TLDA 
detection assay, which quantifies expression of 5 NB specific mRNAs in bone and bone marrow 
(CHGA, DCX, DDC, PHOX2B, and TH). Blood and bone marrow samples will be submitted at 
baseline and at the time of each disease evaluation following instructions in the NANT Biology 
Study protocol.  Patients can submit only bone marrow for NB5 assay if blood volumes for research 
do not allow for blood submission. 
 
Patients are required to enroll on N04-05, NANT Biology Study.  Refer to N04-05 protocol for 
specimen requirements.  Patients can submit only bone marrow for NB5 assay if blood volumes for 
PK studies do not allow for blood submission for additional studies, as priority for blood volumes is 
given to the PK analyses. 
 
 
 

 
 
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9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL AND OFF STUDY CRITERIA 
 
9.1 
Criteria for Removal from Protocol Therapy 
 
1. Disease Progression Before Active Treatment  
2. Disease Progression, Relapse During Active Treatment 
3. Patient/Parent Withdrawal/Refusal Before Beginning Protocol Therapy 
4. Patient/Parent Withdrawal/Refusal After Beginning Protocol Therapy  
5. Unacceptable Adverse Events By Protocol Criteria  
6. Other Adverse Event / Side Effects / Complications  
7. Patient Off-Treatment For Other Complicating Disease  
8. Initiation Onto Another Therapeutic Study and/or Another Anti-Cancer Therapy 
9. Treatment Completed Per Protocol Criteria  
10. No Treatment  
11. Lost To Follow-Up 
12. Death While On Protocol Therapy  
 
For patients who have ‘disease progression, relapse during active treatment’ may continue treatment with 
lorlatinib beyond the time of imaging-defined disease progression, at the discretion of the investigator, if 
the patient is perceived to be experiencing clinical benefit or to avoid rapid progression associated with 
immediate withdrawal of tyrosin kinase inhibitor therapy. These patients may receive up to one additional 
course of lorlatinib investigational product and may receive radiation treatment during this time, giving the 
treating physician time to secure commercial lorlatinib supply.  
 
Patients who are off protocol therapy are to be followed until they meet the criteria for off study.   Patients 
who are removed from therapy prior to progression will be followed for progressive disease until they 
progress, die, or start another therapy (in which case the date of the new therapy and the type of therapy 
will be recorded).  All patients will be followed until death for survival analysis, unless consent is withdrawn 
or patient is lost to follow-up. Protocol follow-up forms will be completed every 6 months after patient 
comes off protocol therapy for the first year and then once a year thereafter (see data submissions 
schedule for further detail).  
 
9.2 
Off Study Criteria 
 
1. Death 
2. Lost to follow-up 
3. Patient/Parent withdrawal of consent 
 

 
 
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10.0 
STATISTICAL CONSIDERATIONS  
 
Note: This section has been modified to reflect changes to the study design implemented 
in Amendment 7 (dated 10/31/2019). 
 
The main objectives of the study design and statistical analysis are to (1) establish a recommended 
phase 2 dose (RP2D) of single agent lorlatinib in children and adolescents (Cohort A1), (2) to 
establish a RP2D of single agent lorlatinib in adults (Cohort A2), (3) to obtain additional toxicity and 
efficacy information of single agent lorlatinib at the Cohort A1/A2 RP2D in patients ≥ 12 months of 
age up to ≤ 18 years of age (YOA) (expansion cohort B1) and > 18 YOA (expansion cohort A2), 
and (4) to identify RP2D and obtain preliminary toxicity and efficacy information of lorlatinib in 
combination with topotecan/cyclophosphamide in children ≥12 months of age up to ≤ 30 YOA 
(Cohort B2 dose escalation and expansion). 
 
 
  
Cohort A1 will follow a 3+3 dose escalation design with dose levels defined in Table 15a-d. For 
patients enrolled after activation of Amendment 4, no more than two patients can simultaneously 
be enrolled on Course 1 of therapy.   
 
After Amendment 4, Cohort A2 followed a 3+3 dose escalation design independent of that in Cohort 
A1 with dose levels defined in Table 15b. No more than two patients can simultaneously be enrolled 
on Course 1 of therapy.   
 
Once the RP2D of lorlatinib as a single agent dose has been established in Cohort A1, Cohort A1 
will close and expansion Cohort B1 will open to accrual for patients ≥ 12 months of age and up to 
≤ 18 years of age who are unable to tolerate chemotherapy or due to lack of treatment slot on B2.  
 
Once the RP2D of lorlatinib as a single agent dose has been established in Cohort A2, this cohort 
will be expanded at the RP2D to patients > 18 YOA who are ineligible to enroll on cohort B2 due to 
inability to tolerate chemotherapy, or lack of treatment slot on B2, or age > 30 YOA. Cohort A2 
expansion will remain open as long as either Cohort B1 or B2 is open. After Amendment 10, cohort 
A2 expansion will open to enrollment at DL 3A (100mg/day) to collect additional PK, toxicity and 
response data due to concern of toxicities observed in DL4A.   
 
Cohort B1 will be open to enrollment to 6 or more patients until it is reasonably assured that at least 
12 patients who are evaluable for DLT have been enrolled at the Cohort A1 RP2D (Cohorts A1 and 
B1 combined).   
 
After Amendment 7, Cohort B2 will open to enrollment at DL 4B (95 mg/m2) for patients > 12 
months to < 18 years of age (YOA) concurrently with Cohort A1 DL 5 (115 mg/m2). Cohort B2 will 
follow a 3+3 dose escalation design with dose levels defined in Table 15c. In addition to 
successfully completing B2:DL 4B (3+3), in order to advance patients ≥ 12 months of age and up 
to < 18 YOA to DL 5B on B2, Cohort A1 (single agent) at DL5 must have sufficient (n=6) evaluable 
patients enrolled and completed the DLT cycles to declare the single agent tolerable at that dose 
level.  
 
Once the RP2D of lorlatinib as a single agent dose has been established in Cohort A2, patients > 
18 YOA and up to < 30 YOA can enroll on B2 at the A2 RP2D in combination with chemotherapy. 
No dose escalation is planned for patients > 18 YOA on B2. After Amendment 10, this cohort will 
enroll at DL 3A (100 mg/day) while adding 5 additional patients also treated at DL 3A to the Cohort 
A2 expansion. Although we would attempt to do a 3+3 dose evaluation in this cohort, since this is 
a rare population, if the study is otherwise completed this cohort may close after discussion with 
the study management committee.   
 
At the time of preparing Amendment 7, Cohort A1 has completed 4 doses levels (see Table 15a in 
Section 4.2) and began accrual to DL 5.  In Cohort A2, the 1st dose level (DL 3A) is complete and 

 
 
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the 2nd dose level (DL 4A) needs one more patient.  The table below summarizes the current status 
of this trial and the text below summarizes the expected number of patients.  
 
 
Table 26. Status of Trial with Activation of Amendment 7 
Cohort 
Description 
Age Group 
Current Status / 
Lorlatinib 
Dose Level (DL) 
Future Dose Levels / 
Accrual 
Expected Number of 
(Future) Patients 
A1 
Single Agent 
Dose 
Escalation 
Age: ≥12 mos. 
& < 18 yrs. 
Open at DL 5:  
115 mg/m2/day 
No more dose levels.  DL 5 
currently open & if 0-1/6 pts have 
DLT then this will be the RP2D.  
Otherwise DL 4 (95 mg/m2/day) 
will be RP2D (see Table 15a). 
Up to 6 more patients at DL 
5 (based on 3+3 rules).  May 
back fill DL 4 with 1 more 
patient if DL 4 is RP2D. 
A2 
Single Agent 
Dose 
Escalation 
Adult: > 18 yrs. 
Open at DL 4A: 
150 mg/day 
No more dose levels (see Table 
15b).  Currently 1/5 with DLT & will 
enroll 1 more pt.  If 1/6 with DLT, 
then this (DL 4A) will be the adult 
RP2D.  Otherwise DL 3A (100 
mg/day) will be RP2D 
1 more patient. 
Age: ≥12 mos. 
& < 18 yrs. 
With DL5 in A1, 
dose is no longer 
capped based on 
BSA 
No more accrual 
0 
A2 
Single Agent 
Expansion 
Adult: > 18 yrs. 
& who are not 
eligible for B2 
Waiting for A2 
RP2D to be 
determined 
Lorlatinib dose will be RP2D based 
on A2:  DL 4A or DL 3A 
6-12 more patients 
B1 
Single Agent 
Expansion 
Age: ≥12 mos. 
& < 18 yrs. & 
who are not 
eligible for B2 
Waiting for A1 
RP2D to be 
determined 
Lorlatinib dose will be RP2D based 
on A1:  DL 5 or DL 4 
6-12 patients (to ensure 
that there are 12+ evaluable 
patients treated at the 
RP2D for A1) 
B2 
Combined 
with 
Chemotherapy 
Age: ≥12 mos. 
& < 18 yrs. 
Will open at DL 
4B: 95 
mg/m2/day 
- See Table 15c. 
- Enrolling concurrently with A1 
dose escalation 
- If both A1 DL5 and B2 DL 4B are 
both well tolerated (i.e. 0-1/6 
DLT’s), then will escalate to DL 
5B:  115 mg/m2/day 
Based on 3+3 rules with 9 – 
12 patients and 6 – 12 
additional patients for 
expansion 
Age: > 18 yrs. & 
≤30 yrs. 
Waiting for A2 
RP2D to be 
determined 
Lorlatinib dose will be RP2D based 
on A2:  DL 4a or DL 3a (no dose 
escalation in this age group but de-
escalation possible – see Table 
15d) 
6-12  patients 
 
 
Total Sample Size: Following Amendment 7, in Cohort A1, with DL 1, 2, 3 and 4 having been 
preliminarily completed (19 patients enrolled), 6 additional DLT evaluable patients will be required 
to complete dose-escalation with DL 5. In Cohort A2, with 5 patients having been treated at 100 
mg (DL 3A) with no DLT, and 5 patients treated at 150mg (DL 4A), 4 of which had no DLT, therefore 
1 DLT evaluable patient will be required to complete dose-escalation on Cohort A2. If an RP2D is 
established in Cohort A1, then an additional 6-12 DLT evaluable patients will be required in Cohort 
B1, 9-12 DLT evaluable patients will be required in Cohort B2 DL 4B and 5B, and 6-12 evaluable 
patients for Cohort B2 expansion.  Hence, an additional 27-42 DLT evaluable pediatric patients will 
be required to complete Cohorts A1, B1 and B2 combined, and 7-13 to complete Cohort A2 (this 
includes escalation and expansion portion). In all cohorts with dose escalation, 6 DLT-evaluable 
patients will be required to be treated at a dose level before it can be declared the MTD/RP2D. 
Additional patients will be treated at the declared MTD/RP2D as described above to better describe 
toxicity and evaluate the anti-tumor activity of lorlatinib at the declared MTD/RP2D.  

 
 
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Study Duration: We anticipate that 2-3 patients per month will be available for enrollment in Cohorts 
A1, B1, and B2 and half this number for Cohort A2.  Factoring in study suspension for DLT evaluation 
and a 5% non-evaluability rate, this study will likely require 24 to 36 months to complete after 
activation of Amendment 7.  
 
10.1 
ENDPOINTS  
 
10.1.1  Primary Endpoints 
 
Following Amendment #4, the primary endpoint for safety and dose-escalation/de-escalation 
decision is occurrence of DLT*, which is defined as any DLT as defined in section 4.3 that occurs 
during Course 1, and any neuropsychology-related DLT as defined in section 4.3 that occurs during 
Course 2.  DLTs per section 4.3 that occur during Course 2 that are not neuropsychology-related 
will not be considered occurrences of DLT*.   
 
Evaluability for DLT*:  In Cohorts A1, A2, and B1, patients are considered evaluable for DLT* if 
they receive at least 75% of the planned dose (i.e. at least 21 of the planned 28 doses) of lorlatinib 
(and for patients in cohort B2, they receive at least 75% of the planned doses of 
topotecan/cyclophosphamide chemotherapy backbone) during Course 1, and at least 75% of 
planned dose of lorlatinib (and for cohort B2 of backbone chemotherapy) in each of the  Courses 1 
and 2, or if they experience DLT*. Patients who are not evaluable for DLT* will be replaced (for 
Cohorts A1, A2, or B1).    
 
Following Amendment #7, in Cohort B2, only course 1 will be used to define evaluability for DLT 
and 2nd course neuropsychology-related DLT’s will no longer be counted in the decisisons to dose 
escalate, expand, or de-escalate.  
 
Evaluability for 1st Course DLT: In Cohort B2 patients are considered evaluable for 1st course 
DLT if they receive at least 75% of the planned dose (i.e. at least 21 of the planned 28 doses) of 
lorlatinib and they receive at least 75% of the planned doses of topotecan/cyclophosphamide 
chemotherapy backbone during Course 1, or if they experience a 1st course DLT. Patients in Cohort 
B2 who are not evaluable for 1st course DLT will be replaced.    
 
An additional primary endpoint will be the plasma concentrations of lorlatinib measured in all 
patients during the 1st course according to the schedule provided in Section 8.    Based on these 
measurements, the following PK parameters will be estimated (among others):  area under curve 
(AUC), clearance, Cmax, Tmax, and terminal half-life.  
 
10.1.2 Secondary/Clinical Endpoints  
 
 
Secondary toxicity and safety, and efficacy endpoints include: 
1. DLT (per section 4.3) occurring during any course of treatment 
2. CTCAE v4 toxicity occurring during any course of treatment 
3. Tumor response per NANT response criteria (section 11) 
4. Event-free survival (EFS), defined as the time from study entry until disease relapse, 
disease progression, second malignancy, or death from any cause, or until last follow-up 
for patients not experiencing any of these events. 
5. Overall survival (OS), defined as the time from study entry until death from any cause, or 
until last follow-up for patients who are alive at last contact. 
 
 
 

 
 
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10.1.3 Endpoints based on Exploratory Aims 
 
For each patient: 
  
10.1.3.1 Circulating Tumor DNA (ctDNA) 
Circulating tumor DNA will be extracted from the plasma (from peripheral blood) at baseline and at 
the time of each disease evaluation.  The frequency of cell-free ctDNA, as well as the profile of 
acquired somatic mutations will be measured. 
 
10.1.3.2 ALK Alterations and Expression 
Where possible, matched tumor samples (at initial diagnosis and at time of most recent recurrence) 
will be analyzed for ALK alterations (presence of mutations, translocations, copy number changes).  
 
10.1.3.3 Detection of Minimal Residual Disease 
To quantify tumor cells in the blood and/or bone marrow before, during and at the end of therapy 
using the NB5, 5-gene Taqman Low Density Array (TLDA) assay. 
 
In addition, every attempt will be made to establish patient-derived xenografts from the patient 
tumor tissue (obtained at recurrence).  These will become a resource for future study. 
 
10.2    STUDY DESIGN   
 
10.2.1 Cohort A1:  Dose Escalation / Phase 1  
 
Cohort A1 is designed as a dose escalation with 5 dose levels.  Cohort A1 will be closed to accrual 
once the single agent RP2D of lorlatinib is defined for patients under 18 years of age. 
 
After Amendment #4, the primary endpoint for dose escalation/de-escalation is DLT* (section 10.1.1).   
 
The standard 3+3 rules for dose escalation will be used.The maximum tolerated dose (MTD) will be 
the highest dose level tested at which 0/6 or 1/6 patients experience DLT*, with at least 2 patients 
experiencing DLT* at the next higher dose.  If a higher dose level does not exist, then this dose will 
be referred to as the RP2D. The RP2D may be further refined by a comprehensive review and 
comparison of the toxicity, response and PK data of the patients treated at the same dose level during 
dose escalation or expansion. 
 
The 3+3 Dose Escalation Rules Are: 
 
1. 
Three new patients will be enrolled at the current  dose level.  
2. 
If 0/3 patients experiences DLT*, then up to 3 patients will be enrolled at the next higher 
dose level if a higher dose level exists.  If no higher dose level exists, up to 3 additional 
patients will be enrolled at the current dose level.  
3. 
If 1/3 experiences DLT* at current dose level, then up to three additional patients will be 
accrued at the same level.  
a. if 0/3 of the additional patients experience DLT* then up to 3 patients will be 
enrolled at the next higher dose level, if a higher dose level exists.  If no higher 
dose level exists, the current dose level is the highest tested dose (HTD). 
b. If one or more of these three additional patients experiences DLT*, then patient 
entry at that dose level is stopped, the MTD has been exceeded and dose 
escalation will be stopped.  Up to three additional patients will be treated at the 
next lower dose level.  If 6 patients have already been treated at that prior dose, 

 
 
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then enrollment will be halted and the lower dose level is the MTD.  
4. 
If 2 or 3 out of 3 experiences DLT*, then the MTD has been exceeded and up to 3 patients 
will be treated at the next lower dose level, unless 6 patients have already been treated at 
that dose or if no lower dose level exists.  If no lower dose level exists, then dose 
escalation/de-escalation will be halted and no MTD exists.  
Only patients who are evaluable for DLT* will be included in the application of the 3+3 rules above.  
Patients who are not evaluable will be replaced.. 
 
Following determination of the MTD and, following comprehensive review of all patients, and 
provided that other safety considerations are acceptable, it is likely that the MTD or HTD will also 
be labeled the recommended Phase 2 dose (RP2D) and used in cohorts B1 and B2. 
 
Justification of the Use of the Phase 1 Design with the 3+3 Rules.  Given the experience of lorlatinib 
in the treatment of adults, there is knowledge of the drug disposition and potential toxicities.  This 
allows for a rational choice of a limited number of doses.  Thus a design with 5 dose levels (and 
one back-up level: Dose Level -1) based on the adult experience is in keeping with the 
recommendations of Lee, Skolnick and Adamson37.  In addition, simulation studies have shown 
that on average the 3+3 design selects an MTD that has a 10% to 20% chance of DLT38,39.  Taken 
together, the proposed 3+3 design has a reasonable probability of selecting a dose with a low true 
DLT rate (in the 10% to 20%). The expansion cohort will further evaluate the probability of DLT at 
the RP2D.  
 
10.2.2 Cohort A2:  Inclusion of Older Patients (> 18 years of age) or Younger Patients with BSA 
           ≥ 1.73 m2  
 
With Amendment #4 initiated the dose escalation of Cohort A2. Cohort A2 will have 2 stages: a 
dose escalation stage and an expansion stage.  Cohort A2 (expansion) opened at the time that 
Cohort A1 was opened and will continue to enroll while Cohorts B1 and B2 are enrolling. 
 
Initially, Cohort A2 treated all patients with single agent lorlatinib at 100 mg/day, with the provision 
that toxicities, as well as DLT’s, will be reviewed on a per patient basis as well as summarized per 
dose in the aggregate and for patients < 18 years of age and for patients > 18 years – and compared 
to those observed in cohorts A1 and B1.   
 
A2 Escalation: Post Amendment 4, Cohort A2 was planned to  have a dose escalation of 2 doses; 
DL 4A (150mg/day) and DL 5A (200mg/day). Dose escalation was to follow the standard 3+3 rules 
(described in 10.2.1). Once 6 patients are treated at the RP2D (with 0-1/6 DLTs) in this cohort 
(likely to be either DL 4A or 5A), the escalation portion will be completed.   Post Amendment 7 due 
to toxicity observed on DL 4A, no more dose escalation beyond DL 4A was planned and DL 5A 
was eliminated.  With Amendment 7, DL 5A will not be tested. 
 
A2 Expansion: Once the escalation stage is complete, additional patients can be enrolled in the 
A2 expansion cohort at the RP2D from A2 escalation, if they are > 18 YOA. Toxicities, as well as 
DLT’s, will be reviewed on a per patient basis as well as summarized per dose in the aggregate by 
age group and combined. As of Amendment 10, 5 additional patients will be enrolled at DL 3A to 
collect additional PK, toxicity and response data in order to help determine RP2D. 
 
Justification of Number of Patients in Cohort A2.  It is expected that the A2 cohort will enroll a total 
of 20 evaluable patients prior to determination of RP2D. A2 expansion cohort at the RP2D may 
enroll 6 or fewer patients.  If 2 or more of the 1st 6 patients experience a DLT*, this will lead to a 
discussion of the suitability of this dose in these patients with relapsed/refractory neuroblastoma.  
The ages of these patients will also be examined.  Table 27 below summarizes the probability of 
observing 2+ patients with DLT* (exact binomial calculations – identical to those for cohort B1); if 

 
 
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the true probability of DLT* is 0.40 or greater, then there is a high probability (0.77 or more) of 
observing 2+ patients with DLT*, suggesting that the proposed dose may be higher than desired.   
 
 
Table 27:  Probability of 2+ Patients with DLT During Cohort A2 Expansion (with 6 DLT-
Evaluable Patients) 
True 
Probability of 
DLT 
0.05 
0.10 
0.15 
0.20 
0.25 
0.30 
0.35 
0.40 
0.45 
0.50 
Probability of 
Observing 2+ 
DLTs in 6 
Patients 
0.03 
0.11 
0.22 
0.34 
0.47 
0.58 
0.68 
0.77 
0.84 
0.89 
 
 
10.2.3  Cohort B1:  Expansion Cohort at the RP2D in Patients < 18 Years of Age:  Single Agent,  
            Lorlatinib 
    
Cohort B1 will open once the single agent lorlatinib RP2D is established based on Cohort A1.  
Based on data available at the time of Amendment #7, this dose is likely to be either Dose Level 4 
(95 mg/m2/day with 150 mg/day max) or Dose Level 5 (115 mg/m2/day). 
 
 
 
In Cohort B1, the 6 new patients will serve to confirm that lorlatinib at the RP2D established in 
Cohort A1 does not have excessive toxicities. Once the acceptable toxicity profile is confirmed, 
then these 6 patients and the 6 patients treated at the RP2D during Cohort A1 will be combined 
(for a total of 12 DLT*-evaluable patients – and accounting for those patients who were not 
“evaluable for DLT*”) to summarize toxicities overall and anti-tumor activity. 
  
Toxicity Monitoring. In the expansion cohort, we will continue to monitor toxicities and DLT*’s.  
Therefore, if 2+ patients experience DLT* then toxicity data at the RP2D (including all patients), as 
well as at other doses will be reviewed to decide whether the dose, schedule, or the associated 
supportive care requirements should be modified or not.  If a change is made, the protocol will be 
amended.   
 
Justification of Number of Patients in the Expansion Cohort.  The Cohort B1 expansion cohort will 
enroll 6 additional DLT* evaluable patients at the RP2D defined in the dose escalation Cohort A1 
of the study.  If 2 or more of these 6 patients experience a DLT* this will lead to a discussion of the 
suitability of the RP2D for the treatment of future patients. Table 28 below summarizes the 
probability of observing 2+ patients with DLT* (exact binomial calculations); if the true probability 
of DLT* is 0.40 or greater, then there is a high probability (0.77 or more) of observing 2+ patients 
with DLT*, suggesting that the proposed dose may be higher than desired.   
 
Table 28:  Probability of 2+ Patients with DLT During Cohort B1 (with 6 DLT-Evaluable 
Patients) 
True Probability of 
DLT 
0.05 
0.10 
0.15 
0.20 
0.25 
0.30 
0.35 
0.40 
0.45 
0.50 
Probability of 
Observing 2+ DLTs 
in 6 Patients 
0.03 
0.11 
0.22 
0.34 
0.47 
0.58 
0.68 
0.77 
0.84 
0.89 
 
The data from all patients treated at the RP2D (in Cohort A1 and in Cohort B1), will be combined 
for a final summary and listing of toxicities observed.  With 12 patients there is an 86% and 93% 

 
 
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103 
 
 
chance that we will observe a toxicity that occurs in at least 15% and 20% of patients, respectively.  
Thus, with the expansion cohort we will be able to observe common toxicities associated with 
lorlatinib given daily as a single agent.   
 
Similarly, with 12 patients treated at the RP2D, there is a 93% chance that at least one patient will 
experience an objective response, if the true response rate is 20% or greater.  Stated differently, if 
none of the 12 patients experience a response, then we will conclude that the true response rate 
is less than 20% (with a 7% error rate of falsely rejecting lorlatinib as active).   
 
10.2.4 Cohort B2:  Combining Lorlatinib with Topotecan/Cyclophosphamide  
 
With Amendment #7, cohort B2 will open and patients < 18 years of age and > 12 months of age 
will be treated at Dose level B2 4B: Lorlatinib at 95 mg/m2/day max, and cyclophosphamide and 
topotecan at fixed doses. There is one possible dose level escalation in this cohort to Dose level 
B2 5B: Lorlatinib at 115 mg/m2/day with 200 mg/day max, and cyclophosphamide and topotecan 
at the standard fixed doses.  
 
Patients 18-30 years of age will initiate B2 once the RP2D from cohort A2 is identified.  No dose 
escalation will be planned for that age group in the B2. With Amendment 10, this cohort will be 
enrolled at DL 3A concurrently with the enrollment of A2 monotherapy expansion cohort at DL 3A. 
 
Escalation to Dose Level B2 5B for patients < 18 years of age and > 12 months of age when both 
of the following conditions are met:   
 
- 
Only 0/3 or 1/6 patients experiences DLT at Dose Level B2-4B (reflecting the 3+3 rules),  
AND 
- 
In Cohort A1, Lorlatinib at 115 mg/m2/day is established as the RP2D for patients ≥12 
months up to < 18 years of age,  
 
Additonal patients, up to 6 (for a total of 12), can be treated at Dose Level B2 4B, if the RP2D in 
Cohort A1is not yet established and the following criteria below are NOT met: 
 
- 
If 2+ patients in the 1st 6 evaluable patients experience a DLT at Dose level B2 4B 
- 
If 3+ patients in the 1st 9 evaluable patients experience a DLT at Dose level B2 4B  
- 
If 4+ patients in the 1st 12 evaluable patients experience a DLT at Dose level B2 4B  
 
If any of these criteria are met, the cumulative data will be reviewed and a decision will be made to 
(a) continue, (b) modify the regimen, or (c) expand the dose level. If the regimen is modified, the 
protocol will be amended with monitoring rules updated. Operationally, during the 1st 6 patients, 
accrual will be paused to ensure that no more than 3 patients are at risk for DLT; in the 2nd group 
of 6 patients, if there are 2 DLT’s, accrual will be paused to ensure that no more than 3 patients 
are at risk for DLT. 
 
Table 28 below summarizes the probability of observing an excessive number of DLT’s as 
described above (exact binomial calculations); if the true probability of DLT is 0.35 or greater, then 
there is a high probability (0.79 or more) of observing an excessive number of patients with DLT, 
suggesting that the proposed doses may be higher than desired.   
 
Table 29:  Probability of an Excessive Number of DLT’s During Cohort B2 
True Probability of DLT 
0.05 
0.10 
0.15 
0.20 
0.25 
0.30 
0.35 
0.40 
0.45 
0.50 
Probability of Observing 
2+ DLTs in 6, 3+ DLTs in 9, 
or 4+ DLTs in 12 patients 
0.03 
0.13 
0.26 
0.41 
0.56 
0.69 
0.79 
0.87 
0.93 
0.96 

 
 
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104 
 
 
 
10.2.5 Monitoring Plan for Deaths within 30 Days of Last Treatment   
 
Each death after initiating protocol therapy and within 30 days of completion of protocol therapy not 
due to tumor will be reviewed by the NANT Study Management Committee (SMC), reported to 
NANT DSMB and a decision, in consultation with NANT DSMB and IND sponsor, will be made to 
close the trial, modify the trial, or continue unchanged; in addition, it will be determined if the event 
requires that new information be added to the informed consent.  Each death occurring within 30 
days of completing the last dose of lorlatinib regardless of cause will be reviewed and reported to 
the NANT DSMB and to the FDA according to standard procedure.   
 
10.3 
Statistical Analysis 
 
All patients who begin treatment will be accounted for; basic demographic and clinical baseline 
data, number of courses begun, number of courses completed, reason off treatment, reason off 
study, total amounts of lorlatinib received, dose delays and reductions, toxicities (grade, type, 
course, and attribution) experienced, best response, and time to progression will be listed for each 
patient and summarized using standard descriptive methods. 
 
10.3.1 Toxicity    
 
All patients who begin treatment with lorlatinib will be included in the analyses of toxicity and (in 
cohort A1) the selection of the RP2D. Only the application of the 3+3 rules (Cohort A1 and A2) and 
the toxicity monitoring guidelines (Cohorts B1, and B2), will be restricted to the patients who are 
“evaluable for DLT” or “evaluable for DLT*”.   
 
Toxicities will be tabulated and reported according to cohort, dose level, grade, type, course, and 
attribution.  Cumulative incidence curves will be used to estimate the proportion of patients who will 
discontinue therapy for reasons of toxicity or general inability to tolerate the regimen.  In a 
descriptive analysis, the association between toxicity (highest grade hematologic and highest grade 
non-hematologic experienced, hypercholesterolemia, and toxicities occurring in more than 20% of 
patients) and the PK levels measured and PK parameters estimated using graphical methods and 
logistic regression.      
 
10.3.2  Anti-Tumor Activity 
 
10.3.2.1 Tumor Response by NANT Criteria 
 
Tumor response will be assessed according to standard NANT criteria (Section 11).  The primary 
endpoint for response analysis will be Best Overall Response (BOR), defined as the best response 
observed prior to progression or start of another therapy. All eligible patients who receive any 
amount of lorlatinib will be evaluable for BOR and will be included in the primary analysis, except 
for patients who terminate protocol treatment or withdraw from the study for reasons unequivocally 
unrelated to either treatment tolerability or disease progression. Evaluable patients who withdraw 
before any post-enrollment disease evaluations will be considered non-responders in this analysis. 
Additional analyses may restrict to patients who receive at least 75% of prescribed lorlatinib dose 
in the first cycle and have at least one post-enrollment disease evaluation. Point estimates for the 
response rate (proportion of patients who have BOR of PR or better will be calculated, together 
with exact 95% confidence intervals. In addition, BOR of minor response or better will also be 
calculated with exacty 95% confidence intervals.  These will include cohorts A1 and B1 combined, 
for cohort B2, and for cohort A2. In addition, multivariable logistic regression analysis will be 
performed to simultaneously assess the influence of age, BSA, dose, and single agent or 
combination treatment.  
 
 

 
 
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10.3.2.2 Event-Free Survival (EFS) 
 
All eligible patients who receive any amount of lorlatinib will be included in the analysis of EFS; 
initially EFS will be summarized in 3 groups:   patients treated on Levels 1 & 2 combined (if numbers 
permit) in cohort A1, patients treated at the RP2D in cohorts A1 and B1, and patients enrolled in 
cohort B2.  The Kaplan-Meier product limit estimates of the EFS over time will be calculated and 
plotted.  Point estimates and 95% confidence intervals will also be calculated.  If numbers permit, 
EFS will be summarized for patients in cohort A2, in a similar fashion. 
 
10.3.2.3 Overall Survival (OS) 
 
All eligible patients who receive any amount of lorlatinib will be included in the analysis of OS; 
initially OS will be summarized in 3 groups: patients treated on Levels 1 & 2 combined in cohort A1 
(if numbers permit), patients treated at the RP2D in cohorts A1 and B1, and patients enrolled in 
cohort B2.  The Kaplan-Meier product limit estimates of the OS over time will be calculated and 
plotted.  Point estimates and 95% confidence intervals will also be calculated.  If numbers permit, 
OS will be summarized for patients in cohort A2, in a similar fashion. 
 
10.3.3  Pharmacokinetic (PK) Data, and ALK Gene Status (ALK fusion protein, ALK mutation or ALK 
amplification) 
 
The association between PK results and ALK gene status with tumor response, as well as the 
associations between PK results with selected toxicities, will be summarized with standard 
descriptive methods (scatterplots, exact logistic regression, contingency tables).  Although p-values 
will be calculated to assess the strengths of the observed associations, because of the relatively 
small numbers, all patterns will require confirmation. 
 
Routine pharmacokinetic parameters for lorlatinib will be determined using standard methods and 
reported descriptively in aggregate and by assigned dose level.  Parameters to be determined 
include Area under the Curve (AUC), clearance, Cmax, Tmax, and terminal half-life.  
 
The correlative biology studies (in cell-free ctDNA and tumor tissue) are also considered 
descriptive.  For the evaluation of pharmacodynamic markers, the relative change from baseline 
will be reported in aggregate for each marker (predominantly, ctDNA frequency, ALK status in 
ctDNA or tumor tissue) and also by lorlatinib dose level.  Association between modulation of these 
markers and occurrence of any DLT and any clinical response (partial response or better) will then 
be examined qualitatively.   
 
For molecular profiling studies, patients will be grouped into sub-categories according to the 
underlying activating ALK alteration).  Association between sub-category and clinical response 
category (partial response or better vs. non-responder) will then be examined qualitatively.   
 
10.3.3.1 Analysis of NB5 Assay  
 
NB5 assay by TLDA will be used as a measure of tumor load in patients at baseline and while on 
therapy.  For each patient, at each evaluation, the TLDA score (with 40 corresponding to 
undetectable tumor and lower values associated with detectable tumor cells) will be calculated.    
For TLDA scores based on blood and on bone marrow (separately), the baseline values will be 
summarized for all patients and according to amount of tumor measured by longest diameter, Curie 
score, and routine bone marrow morphology (positive or negative).  Standard descriptive 
summaries as well as scatterplots will be used.  Changes (from baseline) in the TLDA scores over 
the course of treatment will be plotted and summarized by dose level and course.   The association 
between the changes in TLDA scores and overall tumor response will also be summarized 
graphically and quantitatively.  If numbers permit, patients will be grouped into sub-categories 
according to the underlying activating ALK alteration).    

 
 
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10.3.4  Cognitive and Behavioral Outcomes at Baseline and Changes with Treatment 
 
These will be descriptive analyses to summarize the status of patients at baseline and then to 
record the changes at the end of Courses 1, 2, 4, 6 and every 4 courses thereafter (see Section 
7.12. and Table 24 above for the specific variables).  Standard descriptive statistics will be used; 
plots of individual patients over time as well as in the aggregate will be presented.  For the majority 
of these standardized tests, parametric methods can be used; if the distribution of the data suggests 
otherwise, nonparametric methods will be used. Of particular interest will be the baseline values, 
the magnitude of changes (if any) and the patient-to-patient variability.  In exploratory analysis, we 
will examine the patterns of cognitive and behavioral functioning and the association of relevant 
demographic and medical variables with change in performance over time. Scatterplots, 
correlations, and regression models (if appropriate) will be used to display and summarize patterns.   
 
10.4    Inclusion of Women and Minorities 
 
The study is open to all participants regardless of gender or ethnicity. Review of accrual to past NANT 
studies of new agents demonstrates the accrual of both genders and all NIH-identified ethnicities to 
such studies. Although we will summarize selected endpoints by gender and race/ethnicity, the 
relatively small number of patients entered into this trial will not permit formal comparisons. 
 
Since this is a Phase I study, the exact total number of patients cannot be known in 
advance.  However, our best guess is that we will enroll about 66 patients.  
 
Table 30: PLANNED ENROLLMENT – N015-02 – Based on 66 Patients 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
2 
3 
0 
0 
5 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
2 
2 
0 
0 
4 
White 
16 
30 
0 
0 
46 
More Than One Race 
0 
0 
0 
0 
0 
Hispanic 
0 
0 
5 
6 
11 
Other 
0 
0 
0 
0 
0 
Unknown 
0 
0 
0 
0 
0 
Total 
20 
35 
5 
6 
66 
 

 
 
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11.0 
NANT RESPONSE CRITERIA V2.0 
 
Overall response will incorporate all three parameters: Soft Tissue Response, Bone Response, 
and Bone Marrow Response with Overall Response defined as outlined in Section 11.6.  Response 
for each parameter and overall response will be reported by the treating site using the criteria below. 
However, the final statistical analysis of response will utilize responses as graded by central review, 
using the same criteria below. 
 
11.1 
Soft Tissue Response Criteria 
 
Soft tissue lesions will be evaluated by CT/MRI, using the definitions of measurable disease from 
the Response Evaluation Criteria in Solid Tumors (RECIST 1.1; European Journal Cancer 45: 228-
247, 2009) modified per the criteria below to define target lesions (lesions which are measurable 
AND evaluable for response). 
 
Note that the response criteria for lymph nodes measured by short axis will only be applied to 
discrete lymph nodes that are not adjacent to the primary site and are not composed of a coalesced 
mass of multiple lymph nodes. Coalesced masses of lymph nodes should be assessed using non-
lymph node criteria and measured using longest dimension. 
 
11.1.1 DEFINITION OF SOFT TISSUE TARGET LESIONS: 
. 
Soft tissue target lesions that will be followed for response must meet criteria 1 and 2 OR criteria 3 
below: 
1. A target lesion must be measurable, defined as a soft tissue lesion that can be accurately 
measured in at least one dimension with a longest diameter ≥ 10mm, or for discrete lymph 
nodes ≥ 15mm on short axis.  (The short axis is measured after identifying the longest diameter 
of a lymph node, and then measuring the longest perpendicular diameter to that as the short 
axis). For coalesced masses of multiple lymph nodes, the longest diameter will be used.  
2. A target lesion must also be MIBG avid OR FDG-PET avid (if tumor known to be MIBG non-
avid), and have a biopsy if required in the eligibility criteria.  If one avid soft tissue or bone 
lesion present at enrollment is biopsied showing neuroblastoma or ganglioneuroblastoma at 
any time point prior to enrollment, then all other avid soft tissue lesions present at enrollment 
are considered target lesions.   
3. A lesion that is measurable but does not have either MIBG or FDG-PET uptake will be 
considered a target lesion if a biopsy done at any time prior to enrollment demonstrates 
neuroblastoma and/or ganglioneuroblastoma. 
 
NOTE: Soft tissue components of bone lesions will be considered measurable soft tissue lesions if 
≥ 10mm in at least one dimension, and target lesions evaluable for response if MIBG avid (or FDG-
PET-avid if tumor known to be MIBG non-avid). 
 
 
Serial measurements of target lesions are to be done with the same method of assessment (either 
CT or MRI) used to characterize each lesion reported at baseline.  The sum of diameters (longest 
for non-nodal lesions and coalesced masses of multiple lymph node, short axis for discrete nodal 
lesions) for all target soft tissue lesions will be calculated and reported as the sum of diameters. 
 
11.1.2 DEFINITION OF NON-TARGET SOFT TISSUE LESIONS: 
 
1. Leptomeningeal tumor and tumor in cerebrospinal fluid cytology. 
2. Lesions that are considered likely to be active tumor by the treating physician based on clinical 
correlation (for example, hepatic and pulmonary nodules) 
 
 
 

 
 
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11.1.3  The following lesions will NOT be followed to evaluate response either as target lesions or non- 
target lesions, if they meet the criteria below AND the treating physician feels they are unlikely to  
represent active tumor (an exception for active tumor will be made for c. below): 
1. Measurable non-lymph node and coalesced masses of lymph node soft tissue lesions ≥ 10mm 
and discrete lymph nodes >15 mm that are not MIBG avid or FDG-PET avid (if tumor known to 
be MIBG non-avid) such as tumor at surgical site and if biopsied did not show neuroblastoma 
or ganglioneuroblastoma. 
2. Non-measurable non-lymph node soft tissue lesions < 10mm or non-measurable discrete 
lymph nodes (defined as lymph nodes >10 to <15mm on short axis). 
3. Intramedullary bone lesions will not be followed for CT/MRI response even though they are felt 
to represent active tumor since they will be evaluated with MIBG scans (or FDG-PET scans if 
MIBG non-avid), and since bone changes on CT/MRI are known to persist after resolution of 
active tumor.   
 
11.1.4  SOFT TISSUE RESPONSE CRITERIA: 
 
11.1.4.1 Complete Response (CR) 
All target and non-target soft tissue lesions have longest diameter < 10 mm. Discrete lymph nodes 
identified as target lesions must decrease to a short axis < 15 mm. Resolution of all MIBG uptake 
(FDG-PET uptake if tumor known to be MIBG non-avid). 
 
11.1.4.2 Partial Response (PR) 
At least a 30% decrease in sum of diameters of target soft tissue lesions (using longest diameter 
for non-nodal and coalesced masses of lymph node lesions and short axis for discrete lymph node 
lesions), taking as reference the measurement of target lesions performed at study enrollment. 
Non-target soft tissue lesions must be stable to smaller in size.  No new lesions.  MIBG (FDG-PET 
for MIBG non-avid tumors) uptake may still be present in lesions positive at enrollment. 
 
11.1.4.3 Progressive Disease (PD) 
At least a 20% increase in sum of diameters of target soft tissue lesions (using longest dimension 
for non-nodal and coalesced masses of lymph node lesions and short axis for discrete lymph node 
lesions) taking as reference the smallest sum of diameters while on study (this includes the baseline 
if that is the smallest while on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of 5 mm. A new target or non-target soft tissue lesion seen on 
CT/MRI without MIBG or PET uptake is considered PD, but may be biopsied to rule out PD.  An 
overall substantial worsening of non-target soft tissue lesions is also considered as a criteria for 
PD (guidance for substantial includes a 73% increase  in volume, or sufficient worsening of overall 
non-target disease such that the treating physician feels a change in therapy is indicated).     
 
New uptake of MIBG (or FDG-PET for MIBG non-avid tumors) at target and/or non-target soft tissue 
lesions which are stable in size, will also be considered PD.  Biopsy of such lesions can be done 
to rule out PD for the MIBG (or FDG-PET) response.   
 
11.1.4.4 Stable disease (SD)  
(Applies only to patients with target soft tissue lesions) 
Neither sufficient shrinkage in sum of diameters to qualify for PR nor does the patient meet any 
criteria for PD. No new soft tissue lesions.  Non-target soft tissue lesions must be stable to smaller 
in size. 
 
11.1.4.5 Stable disease-no target lesions (SD-NTL)   
(Applies to patients with non-target soft tissue lesions only) 
Non-target soft tissue lesions are still present; may be smaller or stable in size, and do not meet 
criteria for PD.  No new soft tissue lesions and no new uptake of MIBG (FDG-PET if tumor known 
to be MIBG non-avid) at existing non-target soft tissue lesions.  New lesions or lesions with new 
MIBG (FDG-PET) uptake may be biopsied to rule out PD. 
 

 
 
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11.1.4.6 Not involved (NI):  No target or non-target soft tissue lesions 
 
11.1.4.7 Not evaluable (NE) 
CT/MRI scans and/or MIBG scans (FDG-PET if tumor known to be MIBG non-avid) are of 
inadequate quality as assessed by central reviewer, or scans are not repeated of all anatomic sites 
with tumor documented at entry. (Note that patients not evaluable at a given time point may be 
evaluable for response at later time points if all scans done with adequate quality at later time 
point) or if based on Study Management Committee / PI review it is deemed that there is insufficient 
data to grade response. 
 
11.1.4.8 Not done (ND) 
 No CT/MRI scans were done at the given time point.  
 
11.2 
Bone Marrow Response Criteria  
 
Methodology:   
1. 
Routine morphology with immunohistochemistry will be used for all bone marrow evaluations.  
Immunohistochemistry (with antibodies that are used per local site’s standard procedure) is 
recommended for evaluating percentage of tumor but it is not required.  If 
immunohistochemistry is not done on the baseline bone marrow, then BM response should 
be graded based on routine morphology only at all time points. 
2. 
The percentage of tumor in the bone marrow at study entry (baseline) and all subsequent time 
points reported will use the highest tumor percentage noted among the four samples (bilateral 
aspirates and biopsies).   
3. 
The percentage of tumor in an aspirate will be calculated as the number of tumor cells divided 
by the number of total nucleated cells.   
4. 
The percentage of tumor in a biopsy will be calculated as the percent of tumor cells (including 
neuroblasts, mature and maturing ganglion cells) based on the bone marrow parenchymal 
surface area examined. Schwannian stroma only is considered negative.  
 
Bone marrow response will be graded using the bone marrow done at study entry as the reference 
point, except for PD, which is graded based on comparison to the most recent bone marrow 
evaluation. The baseline bone marrow must include an attempt to obtain bilateral aspirates and 
biopsies, and will be considered as evaluable if at least one biopsy sample is adequate to determine 
the percentage tumor involvement. At baseline, or any subsequent time point, the percentage tumor 
from the unilateral evaluable biopsy will be used to grade bone marrow response.  Patients with ≤ 
5% tumor (including patients with tumor seen by immunohistochemistry only) on all samples of the 
bilateral bone marrow aspirate and biopsies at the baseline evaluation will be evaluable for bone 
marrow response, but defined separately from patients with > 5% at study entry as outlined below.  
 
Central review will be performed on bilateral biopsies only, unless BM tumor is seen only on 
aspirates.  If a patient meets protocol criteria for central review of BM response, morphology slides 
will be requested.   
 
11.2.1 Complete Response (CR) 
 
Greater than 5% tumor at study entry, with no tumor seen at one subsequent time point 
 
 
11.2.2 Complete Response Minimal Disease (CR-MD)  
 
≤ 5% tumor at study entry, with no tumor seen at one subsequent time point.  
 
11.2.3 Partial Response (PR) 
 
Greater than 20% tumor at study entry, with >0 to < 5% tumor at a subsequent time point.  
 
 
 

 
 
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11.2.4  Minimal Disease (MD) 
 
One of the following: 
1. No tumor at study entry, with >0 to ≤5% tumor at a subsequent time point 
2. >0 to ≤5% tumor at study entry, with >0 to ≤5% tumor at a subsequent time point 
3. >5% tumor at study entry, with >0 to ≤5% at a subsequent time point. 
 
11.2.5 Progressive Disease (PD) 
Patients with any amount of tumor in the bone marrow at study entry will be considered to have PD 
if one subsequent evaluation shows >20% tumor on any one bone marrow sample AND there is a 
greater than 2 times increase in the amount of tumor compared to study entry. 
 
Patients with ≤ 5% tumor at study entry must increase to > 20% tumor to have PD; a patient with 
30% tumor at study entry must increase to >60% tumor.  If patients have an increase in tumor 
amount which is less than the amount specified for PD, the response will be classified as SD.  
 
Patients with no tumor at study entry will be considered PD if ONE subsequent evaluation shows 
>5% tumor.   
 
Patients who are deemed to have bone marrow progression based on review of prior bone marrows 
by physician assessment and confirmed by the study management committee. 
 
11.2.6 Stable Disease (SD) 
Persistence of an amount of tumor in the bone marrow that does not meet criteria for progressive 
disease or PR or MD, and is > 5%.   
 
11.2.7  Not Evaluable (NE) 
Patients for whom follow-up bone marrow evaluations do not include an attempt to obtain bilateral 
aspirates and biopsies and do not have at least one adequate biopsy sample, as assessed by local 
site’s pathology report for that time point or if based on Study Management Committee / PI review 
it is deemed that there is insufficient data to grade response.    
 
11.2.8  Not involved (NI) 
Patients with no evidence of neuroblastoma in the bone marrow at study entry, and bone marrow 
remains negative on any subsequent evaluations.   
 
11.2.9  Not done (ND) 
Bone marrow evaluation not done at a given time point. 
 
 
 

 
 
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11.2.10 EXAMPLES OF GRADING BONE MARROW RESPONSE: 
 
BASELINE 
Time Point 1 or any subsequent time point* 
BM Response 
0 
0 
NI 
0 
>0-<=5 
MD 
0 
>5 
PD 
>0-<=5 
0 
CR-MD 
>0-<=5 
>0-<=5 
MD 
>0-<=5 
>5-20 
SD 
>0-<=5 
>-20 
PD 
>5-20 
0 
CR 
>5-20 
>0-<=5 
MD 
>5-20 
>5-20 
SD 
>5-20 
>-20 and doubled compared to baseline 
PD 
>20 
0 
CR 
>20 
>0-<=5 
PR 
>20 
>5-20 
SD 
>20 
>20 but not doubled compared to baseline 
SD 
>20 
>-20 and doubled compared to baseline 
PD 
 
 
 
 

 
 
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11.3. 
Bone Response Criteria using MIBG scans (for MIBG avid tumors) 
 
Bone response will be evaluated using MIBG scans for MIBG avid tumors.  FDG-PET scans (see 
section 11.4) may be substituted for MIBG scans to assess bone response only if the tumor is 
known to be MIBG non-avid.  Bone response will be graded using a modification of the Curie 
scoring scale (Eur J Cancer 1995;31A:256-261). The treating site will report the Bone Response 
using MIBG scoring done at local site, however the statistical endpoint of Bone Response will utilize 
the MIBG score from the central reviewer. 
 
MIBG scans will be scored for 9 anatomic regions for bone metastases only, MIBG uptake in soft 
tissue disease will NOT be included, since this uptake is utlized as part of evaluating Soft Tissue 
Response.  SPECT scans are strongly encouraged to be used for MIBG scoring, if SPECT is 
available at baseline and subsequent time points.  If SPECT scans are not available at all time 
points, then conjugate planar imaging alone should be used to score each region, and SPECT may 
be used only as an adjunct  to help delineate the location of the MIBG avid lesion. 
 
Each of the 9 regions will be given a score of 0-3, as defined below. 
 
Table 32: Scoring of Bone Disease 
Regions 1 – 9 
Scoring 
MIBG uptake 
0 
No MIBG uptake 
1 
1 focal lesion 
2 
> 1 focal lesion 
3 
> 50% of a region 
 
 
The absolute extension score is obtained by adding the scores of all nine regions.  The presence of a 
MIBG avid lesion, and NOT the “intensity” of MIBG-avidity, determines the scoring within a particular region. 
 
 
 

 
 
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REGIONS 1 – 9 / BONE DISEASE:  Cranio-facial disease is scored in Region 1, cervico-thoracic 
spine in Region 2, ribs / sternum / clavicles / scapula in Region 3, lumbar-sacral spine in Region 4, 
pelvis in Region 5, humeri in Region 6, distal upper extremities in Region 7, femurs in Region 8, 
and distal lower extremities in Region 9 (see figure above). 
 
The relative score is calculated by dividing the absolute score of bone lesions at each time by the 
corresponding pre-treatment overall absolute score. The relative score of each patient is calculated 
at each response assessment and classified as below:  
 
a.   Complete response:  all areas of bone uptake on MIBG scan completely resolved. 
 
b. Partial response: Relative score > 0.1 to < 0.5 
 
c. Stable disease: Relative score  0.5 to < 1.2  
d. Progressive disease:  New bone lesions on MIBG scan compared to most recent prior 
MIBG scan OR a relative score > 1.2.  Biopsy of new lesions may be done to rule out 
progressive 
disease. 
If 
biopsy 
is 
negative 
for 
tumor 
(neuroblastoma 
and/or 
ganglioneuroblastoma), patient will not meet definition of PD.   
 
e.   Not evaluable (NE):  MIBG scan of inadequate quality as assessed by central reviewer. 
 
f.  Not involved (NI): No MIBG avid bone lesions at study entry and subsequent response time 
points. 
g. Not done (ND): MIBG scan not done at a given response time point 
 
11.4 
Bone Response Criteria using FDG-PET scans (only for MIBG non-avid tumors) 
 
Patients known to be non-avid for MIBG should have FDG-PET scans performed for monitoring bone 
response. FDG-PET avid bone lesions will be scored by the presence or absence of a lesion with 
uptake that is two times above background.  For MIBG non-avid patients, uptake of FDG-PET in soft 
tissue lesions will be utilized in the Soft Tissue Response (see section 11.1). 
 
11.4.1  Complete response (CR) 
Resolution of all FDG-PET uptake in all FDG-PET avid bone lesions identified at baseline and no 
new FDG-PET avid bone lesions. 
 
11.4.2  Partial response (PR) 
Reduction of number of bone lesions by FDG-PET by ≥ 50%.  No new FDG-PET avid bone lesions. 
 
11.4.3  Stable disease (SD) 
Changes that do not meet the criteria for PR or PD.   
 
11.4.4  Progressive disease (PD) 
New bone lesions on FDG-PET scan.  Note: biopsy may be done to exclude causes of FDG-PET 
uptake other than tumor.  If biopsy of the new lesion is negative for tumor (neuroblastoma and/or 
ganglioneuroblastoma), patient will not meet definition of PD.   
 
11.4.5  Not evaluable (NE) 
FDG-PET scan of inadequate quality to evaluate bone response or if based on Study Management 
Committee / PI review it is deemed that there is insufficient data to grade response. 
 
11.4.6  Not involved (NI) 
No FDG-PET uptake in bone sites that is two times above background.   
 
11.4.7  Not done (ND) 
FDG-PET scan not done at a given time point. 
 
On central review, FDG-PET avid bone lesions will be evaluated by both the MIBG scoring method 
outlined in Section 11.3 and also by enumeration of lesions to grade bone response. 
 
 

 
 
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11.5 
Urine Catecholamines 
Due to variance with diet and concomitant medications, frequently missing dopamine levels, and 
lack of standardized methodology for this assay, urine catecholamines will not be utilized in grading 
response.  Results of urine catecholamines will not be requested. 
 
11.6 
Definition of Overall Response 
The criteria below will be used to define the overall response for each patient, with consideration of 
all three individual response parameters: Soft tissue Response, Bone Response, and Bone Marrow 
Response. 
 
11.6.1 Complete Response (CR) 
Response of CR or NI for soft tissue and bone, soft tissue with bone marrow response of CR or 
CR-MD.   
 
11.6.2  Complete Response MD (CR-MD) 
Soft tissue and bone response are both NI, with BM response of CR-MD  
 
11.6.3 Partial Response (PR) includes any one of the following: 
1. Response of PR for soft tissue, bone response of PR, and BM response of CR, CR-MD, PR, 
MD, or NI. 
2. Response of CR, SD-NTL or NI for soft tissue, with bone response of PR, and BM response 
of CR, CR-MD, PR, MD, or NI.   
3. Soft tissue response of PR; with bone response of CR or NI; and BM response of CR, CR-
MD, PR, MD, or NI. 
4. CR for soft tissue and bone response, with MD for bone marrow response  
 
11.6.4 Progressive Disease (PD) includes either one of the following: 
1. PD for at least one response parameter, including soft tissue, bone, and bone marrow 
response.  If PD is found by one parameter, the other two parameters are not required to be 
evaluated to define an overall response of PD. 
2. Treating physician grades patient as progressive disease based on clinical assessment 
without radiographic or bone marrow evaluations. 
  
11.6.5 Stable disease (SD)   
Response of stable disease for at least one parameter, with response of SD, NI, MD, or SD-NTL 
for other parameters.   
 
11.6.6  Stable disease-Non-target lesions (SD-NTL) 
Response of SD-NTL for soft tissue, with response of NI for bone and bone marrow.  
 
11.6.7  Minor response (MR) 
Complete response, Complete-MD response, and/or partial response for one parameter (i.e. soft 
tissue, bone, or bone marrow), with response of stable disease for a second parameter and any 
response other than PD for third parameter. 
 
11.6.8  Minimal disease (MD) 
Soft tissue and bone marrow responses are both NI, with bone marrow response of MD. 
 
11.6.9 Not evaluable (NE) 
Response of Not evaluable for one or more response parameters including soft tissue, bone, or bone 
marrow for any parameter that had sites evaluable for response at study enrollment.  However, if one 
parameter is done and demonstrates PD this is defined as an overall response of PD.  The SMC will 
review all patients where one or more parameters were graded as not evaluable, and make the final 
determination if the overall response is evaluable at that time point.  In addition, response may be 
declared not evaluable if review by the Study Management Committee (SMC) that there is insufficient 

 
 
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data to grade response.  The SMC may also declare response at a given time point evaluable if only 
one parameter is missing and was not involved at study enrollment. 
 
11.6.10 No progression  
Baseline status at enrollment was NI for soft tissue response, NI for bone marrow response, NI for 
bone response, and there has NOT been PD for any of the three parameters since on protocol therapy 
 
11.6.11 Not done (ND) 
Response not assessed at this time point.  If only one parameter is not done at a given response time 
point, the SMC and PI will review and make the final determination if the overall response is evaluable 
at that time point. 
 
11.6.12  Summary 
The overall response as assessed at any particular time point based on consideration of each of the 
three parameters as defined above is summarized in the following table: 
 
 
TABLE 33: RESPONSE CATEGORIZATION 
SOFT TISSUE RESPONSE 
BONE RESPONSE 
BONE MARROW RESPONSE 
OVERALL RESPONSE 
CR 
CR 
CR 
CR 
NI 
CR 
CR 
CR 
CR 
NI 
CR 
CR 
NI 
NI 
CR 
CR 
CR 
CR 
CR-MD 
CR 
NI 
CR 
CR-MD 
CR 
CR 
NI 
CR-MD 
CR 
CR 
CR 
NI 
CR 
NI 
CR 
NI 
CR 
CR 
NI 
NI 
CR 
NI 
NI 
CR-MD 
CR-MD 
PR 
CR 
CR 
PR 
SD-NTL 
CR 
CR 
PR 
CR 
PR 
CR 
PR 
SD-NTL 
PR 
CR 
PR 
NI 
PR 
CR 
PR 
PR 
NI 
CR 
PR 
SD-NTL 
NI 
CR 
PR 
PR 
CR 
CR-MD 
PR 
SD-NTL 
CR 
CR-MD 
PR 
CR 
PR 
CR-MD 
PR 
PR 
PR 
CR-MD 
PR 
SD-NTL 
PR 
CR-MD 
PR 
NI 
PR 
CR-MD 
PR 
PR 
NI 
CR-MD 
PR 
SD-NTL 
NI 
CR-MD 
PR 
CR 
CR 
PR 
PR 
PR 
CR 
PR 
PR 
SD-NTL 
CR 
PR 
PR 
PR 
PR 
CR 
PR 
NI 
CR 
PR 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
PR 
PR 
SD-NTL 
PR 
PR 
PR 
NI 
PR 
PR 
PR 
CR 
NI 
PR 
PR 
PR 
NI 
PR 
PR 
SD-NTL 
NI 
PR 
PR 
NI 
NI 
PR 
PR 
CR 
CR 
MD 
PR 
PR 
CR 
MD 
PR 
SD-NTL 
CR 
MD 
PR 
NI 
CR 
MD 
PR 
CR 
PR 
MD 
PR 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
116 
 
 
SOFT TISSUE RESPONSE 
BONE RESPONSE 
BONE MARROW RESPONSE 
OVERALL RESPONSE 
PR 
PR 
MD 
PR 
SD-NTL 
PR 
MD 
PR 
NI 
PR 
MD 
PR 
CR 
NI 
MD 
PR 
PR 
NI 
MD 
PR 
PR 
CR 
NI 
PR 
PR 
PR 
NI 
PR 
SD-NTL 
CR 
NI 
PR 
CR 
PR 
NI 
PR 
SD-NTL 
PR 
NI 
PR 
NI 
PR 
NI 
PR 
PR 
NI 
NI 
PR 
SD 
CR 
CR 
MINOR 
SD 
PR 
CR 
MINOR 
CR 
SD 
CR 
MINOR 
PR 
SD 
CR 
MINOR 
SD 
SD 
CR 
MINOR 
SD-NTL 
SD 
CR 
MINOR 
NI 
SD 
CR 
MINOR 
SD 
NI 
CR 
MINOR 
SD 
CR 
CR-MD 
MINOR 
SD 
PR 
CR-MD 
MINOR 
CR 
SD 
CR-MD 
MINOR 
PR 
SD 
CR-MD 
MINOR 
SD 
SD 
CR-MD 
MINOR 
SD-NTL 
SD 
CR-MD 
MINOR 
NI 
SD 
CR-MD 
MINOR 
SD 
NI 
CR-MD 
MINOR 
SD 
CR 
PR 
MINOR 
SD 
PR 
PR 
MINOR 
CR 
SD 
PR 
MINOR 
PR 
SD 
PR 
MINOR 
SD 
SD 
PR 
MINOR 
SD-NTL 
SD 
PR 
MINOR 
NI 
SD 
PR 
MINOR 
SD 
NI 
PR 
MINOR 
SD 
CR 
MD 
MINOR 
SD 
PR 
MD 
MINOR 
CR 
SD 
MD 
MINOR 
PR 
SD 
MD 
MINOR 
CR 
CR 
SD 
MINOR 
PR 
CR 
SD 
MINOR 
SD 
CR 
SD 
MINOR 
SD-NTL 
CR 
SD 
MINOR 
NI 
CR 
SD 
MINOR 
CR 
PR 
SD 
MINOR 
PR 
PR 
SD 
MINOR 
SD 
PR 
SD 
MINOR 
SD-NTL 
PR 
SD 
MINOR 
NI 
PR 
SD 
MINOR 
CR 
SD 
SD 
MINOR 
PR 
SD 
SD 
MINOR 
CR 
NI 
SD 
MINOR 
PR 
NI 
SD 
MINOR 
SD 
CR 
NI 
MINOR 
SD 
PR 
NI 
MINOR 
CR 
SD 
NI 
MINOR 
PR 
SD 
NI 
MINOR 
NI 
NI 
MD 
MD 
SD 
SD 
MD 
SD 
SD-NTL 
SD 
MD 
SD 
NI 
SD 
MD 
SD 
SD 
NI 
MD 
SD 
SD-NTL 
NI 
MD 
MD 
SD 
SD 
SD 
SD 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
117 
 
 
SOFT TISSUE RESPONSE 
BONE RESPONSE 
BONE MARROW RESPONSE 
OVERALL RESPONSE 
SD-NTL 
SD 
SD 
SD 
NI 
SD 
SD 
SD 
SD 
NI 
SD 
SD 
SD-NTL 
NI 
SD 
SD 
NI 
NI 
SD 
SD 
SD 
SD 
NI 
SD 
SD-NTL 
SD 
NI 
SD 
NI 
SD 
NI 
SD 
SD 
NI 
NI 
SD 
SD-NTL 
NI 
NI 
SD-NTL 
NI 
NI 
NI 
NO PROGRESSION 
PD 
ANY 
ANY 
PD 
ANY 
PD 
ANY 
PD 
ANY 
ANY 
PD 
PD 
NOT EVALUABLE 
ANY EXCEPT PD 
ANY EXCEPT PD 
NOT EVALUABLE* 
ANY EXCEPT PD 
NOT EVALUABLE 
ANY EXCEPT PD 
NOT EVALUABLE* 
ANY EXCEPT PD 
ANY EXCEPT PD 
NOT EVALUABLE 
NOT EVALUABLE* 
NOT EVALUABLE 
NOT EVALUABLE 
NOT EVALUABLE 
NOT EVALUABLE* 
NOT DONE 
NOT DONE 
NOT DONE 
NOT DONE* 
NOT DONE (and required at 
this time point) 
ANY EXCEPT PD 
ANY EXCEPT PD 
NOT DONE* 
ANY EXCEPT PD 
NOT DONE (and 
required at this time 
point) 
ANY EXCEPT PD 
NOT DONE* 
ANY EXCEPT PD 
ANY EXCEPT PD 
NOT DONE (and required at this 
time point) 
NOT DONE* 
** The Study Management Committee will review patients with overall response of Not Evaluable and/or 
Not Done to make the final determination of overall response.   
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
118 
 
 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
12.1 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. Adverse events are reported in a routine manner at scheduled times 
during a trial. (Please follow directions for routine reporting provided in the data collection packet 
for this protocol). Additionally, certain adverse events must be reported in an expedited manner to 
allow for timelier monitoring of patient safety and care. The following sections provide information 
about expedited reporting through the use of a written IND safety report (MedWatch) to the Food 
and Drug Administration (FDA). 
 
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.  A copy of the CTCAEv4 can be downloaded from the CTEP home 
page (http://ctep.cancer.gov).   
 
12.2 
Definitions 
 
Adverse Event (AE): An adverse event means any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. 
 
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  Reasonable possibility means there is evidence to suggest a 
causal relationship between the drug and the adverse event. 
 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction: An adverse event 
or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not available, is not consistent with the risk information described in the general 
investigational plan. 
 
Serious Adverse Events (SAE) or Serious Suspected Adverse Reactions: An adverse event 
or suspected adverse reaction is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
 
Table 34: Severe Adverse Events or Reactions 
Death of Patient 
An event that results in the death of a patient. 
Life-Threatening 
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal 
if it had occurred in a more severe form. 
Hospitalization 
An event that results in an admission to the hospital for any length 
of time.  This does not include an emergency room visit or 
admission to an outpatient facility. 
Prolongation of 
Hospitalization 
An event that occurs while the study patient is hospitalized and 
prolongs the patient’s hospital stay. 
Congenital Anomaly 
An anomaly detected at or after birth or any anomaly that result in 
fetal loss. 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
119 
 
 
Persistent or Significant 
Disability/ Incapacity 
An event that results in a condition that substantially interferes with 
the activities of daily living of a study patient.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, 
influenza, or accidental trauma (e.g., sprained ankle). 
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome 
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the patient and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of patient, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent 
or significant disability/incapacity). Examples of such events 
include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 
Each death after initiating protocol therapy and within 30 days of completion of protocol therapy not due to 
tumor will be submitted to the NANT OPS as an SAE within 48 hours of learning of the death.  
 
SAE reporting is  required within 30 days after patient comes off protocol therapy regardless of attribution 
to protocol therapy.  
 
12.3 
Expedited Serious Adverse Event Reporting to NANT Operations 
 
 
For any serious adverse event, both expected and unexpected: 
 
1. Contact the Study Chairperson and the NANT Operations Center to alert them to 
the existence of the serious adverse event within 24 hours of learning of the event. 
2. Within 48 hours of learning of the event, complete the NANT SAE form online 
through Medidata Rave.  If access to Medidata Rave is unavailable for some 
reason, use the paper SAE form found on the NANT website (see NANT website 
(www.nant.org) and email to NANTstaff@chla.usc.edu.  
3. Follow-up information should be submitted online in an updated report through 
Medidata Rave as soon as relevant information is available. 
 
Copies of all serious adverse event reports will be kept on file in the NANT Operations Center. All 
NANT institutions are to file SAE reports with their Institutional Review Boards according to local 
institutional policy.   
 
12.4 
Expedited Adverse Event Reporting to the FDA 
 
Per CFR 312.32 (c), the sponsor of the IND, Araz Marachelian, MD, must notify the FDA and all 
participating investigators in a written IND safety report of any adverse experience associated with 
use of the drug that is both serious and unexpected.  Each written notification shall be made as 
soon as possible, and in no event later than 15 calendar days after the sponsor’s initial receipt of 
the information.  Each written notification may be submitted on FDA Form 3500A (MedWatch) or 
in a narrative format and must bear prominent identification of its contents, i.e., “IND Safety Report”.  
Follow-up information to a safety report should be submitted as soon as the relevant information is 
available. 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
120 
 
 
The sponsor must also notify FDA by telephone or by facsimile transmission of any unexpected 
fatal or life-threatening experience associated with use of the drug in the clinical studies 
conducted under the IND as soon as possible but in no event later than 7 calendar days after initial 
receipt of the information. 
 
Each telephone call or facsimile transmission to the FDA shall be transmitted to the FDA division that 
has responsibility for review of the IND; a specific contact person is assigned to each IND at the time 
the application is filed, and this will be included in the FDA’s correspondence acknowledging receipt 
of the IND application.   
 
12.5 
NANT Operations Center Role in Expedited Adverse Event Reporting to the FDA and 
Participating Sites   
 
For purposes of this protocol, the MedWatch Report Form (FDA 3500A) will be submitted to the FDA 
by NANT on behalf of the IND sponsor, Araz Marachelian, MD.  These forms will be submitted to the 
appropriate FDA division and will serve as the written IND safety report.  The NANT Operations 
Center will file all expedited adverse event reports as well as other adverse events with the FDA and 
other relevant authorities or investigators.  The IND sponsor, Araz Marachelian, MD, has also 
delegated to the NANT Operations Center the telephone/facsimile FDA notification responsibilities 
for unexpected fatal or life-threatening experiences.  All IND submissions will be maintained in a 
master file at the NANT Operations Center. 
 
For Adverse Events associated with the use of the drug that are both Serious and Unexpected: 
 
1. The MedWatch form will be drafted by the NANT Operations Center based on the SAE form within 
10 days of the adverse event and reviewed with PI at treating site and the study chair.  Final 
MedWatch form will be submitted to FDA by NANT Operations Center.  Electronic version of 
MedWatch form is 
available from NANT Operations Center 
or MedWatch 
website 
www.fda.gov/medwatch. NANT will forward the completed report to the FDA and other relevant 
authorities or investigators on behalf of the IND Sponsor, Araz Marachelian, MD.  
 
2. Follow-up information should be submitted as soon as relevant information is available. 
 
For Adverse Events associated with the use of the drug that are Unexpected or Life Threatening: 
 
1. Notify the NANT Operations Center (who will notify the FDA and other relevant authorities and 
investigators) by telephone or fax as soon as possible but no later than 7 calendar days from the 
occurrence of the event. 
 
FDA PHONE: 
1-800-332-1088 
FDA FAX: 
1-800-332-0178 
 
2. The MedWatch form will be drafted by the NANT Operations Center based on the SAE form within 
10 days of the adverse event and reviewed with PI at treating site and the study chair.  Final Medwatch 
form will be submitted to FDA and other relevant authorities or investigators by NANT Operations 
Center on behalf of the IND Sponsor, Araz Marachelian, MD.   
3. Follow-up information should be submitted as soon as relevant information is available. 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
121 
 
 
A cover letter to accompany the MedWatch report will be prepared by the NANT Operations Center in 
collaboration with the IND sponsor, Araz Marachelian, MD. The cover letter will be submitted with 
MedWatch report to the FDA and other NANT institutions and relevant authorities.  Contents will include: 
 
1. An assessment of the adverse event and its significance/relevance to the study. And the impact on 
the risk/benefit ratio of the study. 
2. A statement as to whether this adverse event has been reported previously, and if so, whether the 
frequency is considered unusually high. 
3. A statement as to whether the protocol and/or informed consent should reflect changes in the 
potential risks involved. 
 
Copies of all adverse event reports will be kept on file in the NANT Operations Center.  All NANT 
institutions are to file AE reports with their Institutional Review Boards according to local 
institutional policy.  
 
12.6  
Adverse event reporting requirements for Pfizer Inc.  
 
NANT Operations Center will notify Pfizer, Inc. of all serious adverse events, both expected and 
unexpected, and a copy of all MedWatch forms and related correspondence within 24 hours of first 
awareness of an SAE. 
 
12.7 
Reporting Secondary AML/MDS 
 
Within two weeks of an AML/MDS diagnosis or other secondary malignancy following treatment for 
cancer, submit the following to the NANT Operations Center: 
 
1. A completed NANT SAE Form 
2. A copy of the pathology report confirming the AML/MDS or other malignancy 
3. A copy of the cytogenetics report (if applicable) 
 
The NANT Operations Center will submit the form and accompanying reports to the FDA via 
MedWatch and to Araz Marachelian, MD (IND Sponsor). All NANT institutions are to file the 
secondary malignancy reports with their Institutional Review Boards according to local 
institutional policy. 
 
12.8   
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and must permanently discontinue study drug(s).  All 
pregnancies and suspected pregnancies will be reported to by the NANT Operations Center (see 
Section 12.4 for contact information) immediately.  If a female partner of a male patient becomes 
pregnant during the male patient’s participation in this study, this must be reported to by the NANT 
Operations Center immediately.  
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
122 
 
 
13.0 
RECORDS AND REPORTING 
 
See separate Data Forms Packet which includes the data submission schedule in the member 
section on the NANT web site (www.NANT.org). 
 
The following are required to be submitted for all patients entered: 
 
1. Study case report forms, bone marrow reports (including aspirate and biopsy reports), 
urine catecholamine reports, and radiology reports (CT/MRI/MIBG/PET scans). Study 
case report form data is collected and accessed remotely through Medidata Rave. 
Disease response reports detail reports (CT/MRI, MIBG/PET, Bone marrow, urine 
catecholamines) are sent by email as electronic files to NANTCRF@chla.usc.edu at the 
end of each course of therapy.   
2. For all patients on study, CT/MRI and MIBG/PET scans and bone marrow biopsy slides 
done as baseline tumor evaluation at study entry may be submitted for central review 
upon the request of the NANT Operations Center.  Bone marrow aspirate slides will be 
submitted only upon the request of the NANT Operations Center.  
3. For all patients who report an overall response of Complete Response and Partial 
Response, will submit all CT/MRI scans, MIBG scans, PET scans, and bone marrow 
biopsy slides done, for central review upon request by NANT Operations Center. For all 
patients who report an overall response of Minor Response and Stable Disease will 
submit the aforementioned imaging scans and bone marrow biopsy slides of involved 
disease sites for central review upon request by NANT Operations Center. Additional 
scans and bone marrow aspirate slides may also be requested by the NANT Operations 
Center to clarify response.     
4. Radiology scans are submitted into NANT PACS electronic repository, which is managed 
by the ICL (Imaging Core Lab) at Children’s Hospital Los Angeles.  The Imaging 
CoreGrid DICOM Dropbox software is functional at all NANT sites and is used for all 
NANT clinical trials for central review of tumor response. (See NANT SOP regarding 
Central Review of Response Procedures for details).    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
123 
 
 
 
14.0 
REFERENCES 
 
 
1. 
Chen Y, Takita J, Choi YL, et al: Oncogenic mutations of ALK kinase in neuroblastoma. 
Nature 455:971-4, 2008 
 
2. 
George RE, Sanda T, Hanna M, et al: Activating mutations in ALK provide a therapeutic 
target in neuroblastoma. Nature 455:975-8, 2008 
 
3. 
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 
 
4. 
Mosse YP, Laudenslager M, Longo L, et al: Identification of ALK as a major familial 
neuroblastoma predisposition gene. Nature 455:930-5, 2008 
 
5. 
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 
 
6. 
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. The lancet oncology 14:472-80, 2013 
 
7. 
Tucker ER, Danielson LS, Innocenti P, et al: Tackling crizotinib resistance: The pathway 
from drug discovery to the pediatric clinic. Cancer Res. 75:2770-2774, 2015 
 
8. 
Chand D, Yamazaki Y, Ruuth K, et al: Cell culture and Drosophila model systems define 
three classes of anaplastic lymphoma kinase mutations in neuroblastoma. Disease models & 
mechanisms, 2013 
 
9. 
Goodman M, Gurney J, Smith M, et al: Sympathetic Nervous System Tumors, in Ries L, 
Smith M, Gurney J, et al (eds): Cancer Incidence and Survival among Children and Adolescents: United 
States 
SEER Program 1975-1995, National Cancer Institute, SEER Program. Bethesda, National Institutes of 
Health, 1999, pp 65-72 
 
10. 
Seeger RC, Brodeur GM, Sather H, et al: Association of multiple copies of the N-myc 
oncogene with rapid progression of neuroblastomas. New England Journal of Medicine 313:1111-1116, 
1985 
 
11. 
Wang LL, Suganuma R, Ikegaki N, et al: Neuroblastoma of undifferentiated subtype, 
prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: a report 
from the Children's Oncology Group. Cancer 119:3718-26, 2013 
 
12. 
Yu AL, Gilman AL, Ozkaynak MF, et al: Anti-GD2 antibody with GM-CSF, interleukin-2, 
and isotretinoin for neuroblastoma. The New England journal of medicine 363:1324-34, 2010 
 
13. 
Smith MA, Seibel NL, Altekruse SF, et al: Outcomes for children and adolescents with 
cancer: challenges for the twenty-first century. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 28:2625-34, 2010 
 
14. 
Chen Y, Takita J, Choi Y, et al: Oncogenic mutations of ALK kinase in neuroblastoma. 
Nature 455:971-974, 2008 
 
15. 
George R, Sanda T, Hanna M, et al: Activating mutations in ALK provide a therapeutic 
target in neuroblastoma. Nature 455:975-978, 2008 
 
16. 
Bresler SC, Weiser DA, Huwe PJ, et al: ALK Mutations Confer Differential Oncogenic 
Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma. Cancer Cell 26:682-694, 2014 
 
17. 
Eleveld TF, Oldridge DA, Bernard V, et al: Relapsed neuroblastomas show frequent 
RAS-MAPK pathway mutations. Nat Genet 47:864-71, 2015 
 
18. 
Padovan-Merhar OM, Raman P, Ostrovnaya I, et al: Enrichment of targetable mutations 
in the relapsed neuroblastoma genome. PLoS One, In press 
 
19. 
Schleiermacher G, Javanmardi N, Bernard V, et al: Emergence of New ALK Mutations at 
Relapse of Neuroblastoma. J Clin Oncol 32:2727-34, 2014 
 
20. 
Eleveld TF, Oldridge DA, Bernard V, et al: Relapsed neuroblastomas show frequent 
RAS-MAPK pathway mutations. Nat Genet, 2015 
 
21. 
Hallberg B, Palmer RH: Mechanistic insight into ALK receptor tyrosine kinase in human 
cancer biology. Nat. Rev. Cancer 13:685-700, 2013 
 
22. 
Sun Y, Nowak KA, Zaorsky NG, et al: ALK inhibitor PF02341066 (crizotinib) increases 
sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK. Mol Cancer Ther 12:696-704, 
2013 

 
 
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124 
 
 
 
23. 
Zou HY, Friboulet L, Kodack DP, et al: PF-06463922, an ALK/ROS1 Inhibitor, 
Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell 
28:70-81, 2015 
 
24. 
Zou HY, Li Q, Engstrom LD, et al: PF-06463922 is a potent and selective next-generation 
ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proc Natl Acad Sci U S A 
112:3493-8, 2015 
 
25. 
Johnson TW, Richardson PF, Bailey S, et al: Discovery of (10R)-7-amino-12-fluoro-
2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(m etheno)pyrazolo[4,3-h][2,5,11]-
benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic 
lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-
spectrum potency against ALK-resistant mutations. J Med Chem 57:4720-44, 2014 
 
26. 
Kramer K, Kushner B, Heller G, et al: Neuroblastoma metastatic to the central nervous 
system.  The Memorial Sloan-Kettering Cancer Center experience and a literature review. Cancer 
91:1510-1519, 2001 
 
27. 
Infarinato NR, Park JH, Krytska K, et al: The ALK/ROS1 Inhibitor PF-06463922 
Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma. Cancer Discov 6:96-107, 
2016 
 
28. 
Shaw AT, Felip E, Bauer TM, et al: Lorlatinib in non-small-cell lung cancer with ALK or 
ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. 
Lancet Oncol 18:1590-1599, 2017 
 
29. 
Bettegowda C, Sausen M, Leary RJ, et al: Detection of circulating tumor DNA in early- 
and late-stage human malignancies. Sci Transl Med 6:224ra24, 2014 
 
30. 
Diaz LA, Jr., Bardelli A: Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 
32:579-86, 2014 
 
31. 
Cheung NK, Zhang J, Lu C, et al: Association of age at diagnosis and genetic mutations 
in patients with neuroblastoma. JAMA 307:1062-71, 2012 
 
32. 
Molenaar JJ, Koster J, Zwijnenburg DA, et al: Sequencing of neuroblastoma identifies 
chromothripsis and defects in neuritogenesis genes. Nature 483:589-93, 2012 
 
33. 
Pugh TJ, Morozova O, Attiyeh EF, et al: The genetic landscape of high-risk 
neuroblastoma. Nature Genetics 45:279-84, 2013 
 
34. 
Bresler SC, Weiser DA, Huwe PJ, et al: ALK Mutations Confer Differential Oncogenic 
Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma. Cancer Cell 26:682-694, 2014 
 
35. 
Sausen M, Leary RJ, Jones S, et al: Integrated genomic analyses identify ARID1A and 
ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet 45:12-7, 2013 
 
36. 
Martinsson T, Eriksson T, Abrahamsson J, et al: Appearance of the novel activating 
F1174S ALK mutation in neuroblastoma correlates with aggressive tumor progression and 
unresponsiveness to therapy. Cancer Res 71:98-105, 2011 
 
37. 
Lee DP, Skolnik JM, Adamson PC: Pediatric phase I trials in oncology: an analysis of 
study conduct efficiency. J Clin Oncol 23:8431-41, 2005 
 
38. 
Surriga O, Rajasekhar VK, Ambrosini G, et al: Crizotinib, a c-Met inhibitor, prevents 
metastasis in a metastatic uveal melanoma model. Mol Cancer Ther 12:2817-26, 2013 
 
39. 
Zheng X, He K, Zhang L, et al: Crizotinib induces PUMA-dependent apoptosis in colon 
cancer cells. Mol Cancer Ther 12:777-86, 2013 
 
40. 
Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for 
neuroblastoma diagnosis, staging, and response to treatment. Journal of Clinical Oncology 11:1466-
1477, 1993 
 
41. 
Duffaud F, Therasse P: [New guidelines to evaluate the response to treatment in solid 
tumors]. Bulletin du cancer 87:881-6, 2000 
 
42. 
Ady N, Zucker JM, Asselain B, et al: A new 123I-MIBG whole body scan scoring method-
-application to the prediction of the response of metastases to induction chemotherapy in stage IV 
neuroblastoma. European journal of cancer 31A:256-61, 1995 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
125 
 
 
APPENDIX I: 
PERFORMANCE STATUS SCALES/SCORES 
 
Performance Status Criteria 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to 
carry on all pre-disease 
performance without 
restriction. 
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. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to 
carry out work of a light 
or sedentary nature, 
e.g., light housework, 
office work. 
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. 
2 
Ambulatory and capable 
of all self-care but 
unable to carry out any 
work activities. Up and 
about more than 50% of 
waking hours 
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. 
3 
Capable of only limited 
self-care, confined to 
bed or chair more than 
50% of waking hours.  
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. 
4 
Completely disabled. 
Cannot carry on any 
self-care. Totally 
confined to bed or chair. 
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. 
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.  
 
  
 

 
 
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APPENDIX II: BLOOD VOLUME SUMMARY FOR CORRELATIVE STUDIES 
 
Blood volumes below are maximum values. For patients with a weight below the minimum required to 
tolerate all blood draws requested for correlative studies, please consult with study chair to determine 
prioritization of samples. 
 
 
Lorlatinib 
Pharmacokinetics 
Pharmacodynamic 
Studies (ctDNA)** 
Biology Study (NB5 
Assay)* 
3.0 mL in K2EDTA (lavender top) 
8.5 mL in Streck Cell-
Free DNA BCT tube 
Refer to N04-05 protocol for 
collection requirements 
Course 
Day 
Sample Time Points 
 
 
Entry 
(baseline) 
 
 
17 mL 
Blood & 
bone marrow aspirate 
1 
1 
0 hour (pre-
dose)  
3.0 mL 
 
 
1 
1 hour 
3.0 mL 
 
 
1 
2 hour 
3.0 mL 
 
 
2 
24 hour (pre-
2nd dose) 
3.0 mL 
 
 
 
 
 
15 
Pre-dose; 1 
hr; 2hr; 4hr; 
6hr 
3.0 mL 
 
 
 
 
2 
End of 
course 
 
17 mL 
Blood & 
bone marrow aspirate 
4 
End of 
course 
 
17 mL 
Blood & 
bone marrow aspirate 
6+ 
(corresponding 
with disease 
evaluations) 
End of 
course 
 
17 mL 
Blood & 
bone marrow aspirate 
End of 
therapy 
 
Blood & 
bone marrow aspirate 
*If > 10kg: four green tops (16ml); if < 10kg: three green tops (12ml). Bone marrow = two green tops (one 
for each side)   
**When ctDNA and biology samples coincide, the priority is to collect the ctDNA first and if maximum volume 
of blood patient consented has not surpassed then collect biology sample. 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
127 
 
 
APPENDIX III: DOSING NOMOGRAMS 
 
Lorlatinib Dose Assignment:   
Dose level -1 
30 mg/m2 
(available in 5 mg, 25 mg tablets) 
 
Daily Dose Given to a Patient 
Number of Pills 
BSA (m2) 
Daily Dose 
(mg) 
Equivalent 
Dose (mg/m2) 
#Pills  
5 mg 
#Pills  
25 mg 
#Pills 
Total 
0.50 - 0.58 
15 
25.9-30 
3 
0 
3 
0.59 - 0.74 
20 
27 – 33.9 
4 
0 
4 
0.75 - 0.91 
25 
27.5-33.3 
0 
1 
1 
0.92-1.08 
30 
27.8-32.6 
1 
1 
2 
1.09-1.24 
35 
28.2-32.1 
2 
1 
3 
1.25-1.41 
40 
28.4-32 
3 
1 
4 
1.42-1.58 
45 
28.5-31.7 
4 
1 
5 
1.59-1.72 
50 
29.1-31.4 
0 
2 
2 
 ≥1.73 
100 
<57.8 
Treat on Cohort A2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Lorlatinib Dose Assignment: Dose level 1 
45 mg/m2 
(available in 5 mg, 25 mg tablets) 
 
Daily Dose Given to a Patient 
Number of Pills 
BSA (m2) 
Daily Dose 
(mg) 
Equivalent 
Dose (mg/m2) 
#Pills  
5 mg 
#Pills  
25 mg 
#Pills 
Total 
0.50 - 0.61 
25 
41.0 - 50.0 
0 
1 
1 
0.62 - 0.72 
30 
41.7 - 48.4 
1 
1 
2 
0.73 - 0.83 
35 
42.2 - 47.9 
2 
1 
3 
0.84 - 0.94 
40 
42.6 - 47.6 
3 
1 
4 
0.95 - 1.05 
45 
42.9 - 47.4 
4 
1 
5 
1.06 - 1.16 
50 
43.1 - 47.2 
0 
2 
2 
1.17 - 1.27 
55 
43.3 - 47.0 
1 
2 
3 
1.28 - 1.38 
60 
43.5 - 46.9 
2 
2 
4 
1.39 - 1.49 
65 
43.6 - 46.8 
3 
2 
5 
1.50 - 1.61 
70 
43.5 - 46.7 
4 
2 
6 
1.62 - 1.72 
75 
43.6 - 46.3 
0 
3 
3 
 ≥1.73 
100 
< 57.8 
Treat on Cohort A2 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Lorlatinib Dose Assignment: Dose level 2 
60 mg/m2 
(available in 5 mg, 25 mg tablets) 
Daily Dose Given to a Patient 
Number of Pills 
BSA (m2) 
Daily Dose 
(mg) 
Equivalent 
Dose (mg/m2) 
#Pills  
5 mg 
#Pills  
25 mg 
#Pills 
Total 
0.50 - 0.54 
30 
55.6 - 60.0 
1 
1 
2 
0.55 - 0.62 
35 
56.5 - 63.6 
2 
1 
3 
0.63 - 0.70 
40 
57.1 - 63.5 
3 
1 
4 
0.71 - 0.79 
45 
57.0 - 63.4 
4 
1 
5 
0.80 - 0.87 
50 
57.5 - 62.5 
0 
2 
2 
0.88 - 0.95 
55 
57.9 - 62.5 
1 
2 
3 
0.96 - 1.04 
60 
57.7 - 62.5 
2 
2 
4 
1.05 - 1.12 
65 
58.0 - 61.9 
3 
2 
5 
1.13 - 1.20 
70 
58.3 - 61.9 
4 
2 
6 
1.21 - 1.29 
75 
58.1 - 62.0 
0 
3 
3 
1.30 - 1.37 
80 
58.4 - 61.5 
1 
3 
4 
1.38 - 1.45 
85 
58.6 - 61.6 
2 
3 
5 
1.46 - 1.54 
90 
58.4 - 61.6 
3 
3 
6 
1.55 - 1.62 
95 
58.6 - 61.3 
4 
3 
7 
1.63 - 1.72 
100 
57.8 - 61.3 
0 
4 
4 
≥1.73 
100 
< 57.8 
Treat on Cohort A2  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
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Lorlatinib Dose Assignment: Dose level 3 
 75 mg/m2 
(available in 5 mg, 25 mg tablets) 
Daily Dose Given to a Patient 
Number of Pills 
BSA (m2) 
Daily Dose 
(mg) 
Equivalent 
Dose (mg/m2) 
#Pills  
5 mg 
#Pills  
25 mg 
#Pills 
Total 
0.50 - 0.56 
40 
71.4 - 80.0 
3 
1 
4 
0.57 - 0.63   
45 
71.4 - 78.9 
4 
1 
5 
0.64 - 0.69 
50 
72.5 - 78.1 
0 
2 
2 
0.70 - 0.76 
55 
72.4 - 78.6 
1 
2 
3 
0.77 - 0.83 
60 
72.3 - 77.9 
2 
2 
4 
0.84 - 0.89 
65 
73.0 - 77.4 
3 
2 
5 
0.90 - 0.96 
70 
72.9 - 77.8 
4 
2 
6 
0.97 - 1.03 
75 
72.8 - 77.3 
0 
3 
3 
1.04 - 1.10 
80 
72.7 - 76.9 
1 
3 
4 
1.11 - 1.16 
85 
73.3 - 76.6 
2 
3 
5 
1.17 - 1.23 
90 
73.2 - 76.9 
3 
3 
6 
1.24 - 1.29 
95 
73.6 - 76.6 
4 
3 
7 
1.30 - 1.42 
100 
70.4 - 76.9 
0 
4 
4 
1.43 – 1.72 
100 
58.1 – 69.9 
Treat on Cohorts A2 (only when A1 
is open to dose level 3) or B1 or B2 
≥1.73 
100 
< 57.8 
Treat on Cohort A2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
131 
 
 
Lorlatinib Dose level 4 and 4B: 95 mg/m2 (available in 5 mg, 25 mg tablets) 
Daily Dose Given to a Patient 
Number of Pills 
BSA (m2) 
Daily Dose 
(mg) 
Equivalent 
Dose (mg/m2) 
#Pills  
5 mg 
#Pills  
25 mg 
#Pills 
Total 
0.50 – 0.55 
50 
90.9 - 100 
0 
2 
2 
0.56 – 0.60  
55 
91.7 – 98.2 
1 
2 
3 
0.61 – 0.65  
60 
92.3 – 98.4 
2 
2 
4 
0.66 – 0.71  
65 
91.6 – 98.5 
3 
2 
5 
0.72 – 0.76  
70 
92.1 – 97.2 
4 
2 
6 
0.77 – 0.81  
75 
92.6 – 97.4 
0 
3 
3 
0.82 – 0.86 
80 
93.0 – 97.6 
1 
3 
4 
0.87 – 0.92  
85 
92.4 – 97.7 
2 
3 
5 
0.93 – 0.97  
90 
92.8 – 96.8 
3 
3 
6 
0.98 – 1.02 
95 
93.1 – 96.9 
4 
3 
7 
1.03 – 1.07 
100 
93.5 – 97.1 
0 
4 
4 
1.08 – 1.13 
105 
92.9 – 97.2 
1 
4 
5 
1.14 – 1.18 
110 
93.2 – 96.5 
2 
4 
6 
1.19 – 1.23 
115 
93.5 – 96.6 
3 
4 
7 
1.24 – 1.28 
120 
93.75 – 96.8 
4 
4 
8 
1.29 – 1.34 
125 
93.3 – 96.9 
0 
5 
5 
1.35 – 1.39 
130 
93.5 – 96.3 
1 
5 
6 
1.40 – 1.44 
135 
93.8 – 96.4 
2 
5 
7 
1.45 – 1.50 
140 
93.3 – 96.6 
3 
5 
8 
1.51 – 1.55 
145 
93.5 – 96.0 
4 
5 
9 
≥1.56  
150 
≤ 96.2 
0 
6 
6 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
132 
 
 
Lorlatinib Dose Level 5 and 5B: 115 mg/m2  (available in 5 mg, 25 mg tablets) 
Daily Dose Given to a Patient 
Number of Pills 
BSA (m2) 
Daily Dose (mg) 
Equivalent Dose 
(mg/m2) 
#Pills  
5 mg 
#Pills  
25 mg 
#Pills 
Total 
0.50 – 0.54 
60 
111.1 – 120 
2 
2 
4 
0.55 – 0.58 
65 
112.1 – 118.2 
3 
2 
5 
0.59 – 0.63 
70 
111.1 – 118.6 
4 
2 
6 
0.64 – 0.67 
75 
111.9 – 117.2 
0 
3 
3 
0.68 – 0.71  
80 
112.7 – 117.6 
1 
3 
4 
0.72 – 0.76 
85 
111.8 – 118.1 
2 
3 
5 
0.77 – 0.80 
90 
112.5 – 116.9 
3 
3 
6 
0.81 – 0.84 
95 
113.1 – 117.3 
4 
3 
7 
0.85 – 0.89 
100 
112.4 – 117.6 
0 
4 
4 
0.90 – 0.93  
105 
112.9 – 116.7 
1 
4 
5 
0.94 – 0.97  
110 
113.4 – 117.0  
2 
4 
6 
0.98 – 1.02  
115 
112.7 – 117.3 
3 
4 
7 
1.03 – 1.06 
120 
113.2 – 116.5 
4 
4 
8 
1.07 – 1.10 
125 
113.6 – 116.8 
0 
5 
5 
1.11 – 1.15 
130 
113.0 – 117.1 
1 
5 
6 
1.16 – 1.19 
135 
113.4 – 116.4 
2 
5 
7 
1.20 – 1.23 
140 
113.8 – 116.7 
3 
5 
8 
1.24 – 1.28 
145 
113.3 – 116.9 
4 
5 
9 
1.29 – 1.32 
150 
113.6 – 116.3 
0 
6 
6 
1.33 – 1.36  
155 
114.0 – 116.6 
1 
6 
7 
1.37 – 1.41  
160 
113.5 – 116.8 
2 
6 
8 
1.42 – 1.45 
165 
113.8 – 116.2 
3 
6 
9 
1.46 – 1.50  
170 
113.3 – 116.4 
4 
6 
10 
1.51 – 1.54 
175 
113.6 – 115.9  
0 
7 
7 
1.55 – 1.58 
180 
114.0 – 116.1 
1 
7 
8 
1.59 – 1.63 
185 
113.5 – 116.4 
2 
7 
9 
1.64 – 1.67 
190 
113.8 – 115.9 
3 
7 
10 
1.68 – 1.71  
195 
114.0 – 116.1 
4 
7 
11 
≥1.72  
200 
≤ 116.3 
0 
8 
8 

 
 
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133 
 
 
APPENDIX IV: NEUROPSYCHOLOGICAL ADMINISTRATION PROCEDURES BY AGE GROUP 
 
Age at 
Testing 
(Years: 
Months) 
Patient Testing/Self Report 
Parent Report 
Duration of 
Testing for 
Parents 
 
Duration of 
Testing for 
Patients 
1:1 to 1:11 
 
1. Bayley-III  
*(only at baseline, end of course 
2, 6, 10 and then every 8 courses 
+/-5 days for duration of 
treatment) 
1. ABAS-3 Parent/Primary 
Caregiver Form (Ages 0-
5) 
2. PedsQL Infant Scales 
(13-24 months) 
*(standard neuropsych 
observation schedule)  
~ 20 minutes 
 
~ 60 - 90 
minutes 
2:0 – 2:11 
1. Bayley-III  
*(only at baseline, end of course 
2, 6, 10, and then every 8 courses 
+/- 5 days for duration of 
treatment) 
1. ABAS-3 Parent/Primary 
Caregiver Form (Ages 0-
5) 
2. BASC-3 Parent Rating 
Scales-Preschool (Ages 
2-5) 
3. BRIEF- Preschool 
Version 
4. PedsQL Generic Version 
– Parent Report for 
Toddlers (Ages 2-4) 
5. PedsQL 
Multidimensional Fatigue 
Parent Report for 
Toddlers (Ages 2-4) 
*(standard neuropsych 
observation schedule) 
 
 
 
 
 
~ 50 minutes 
 
 
 
 
 
 
 
 
 
 
 
 
 
~ 60 - 90 
minutes 
3:0 – 4:11 
1. Cogstate  
(Detection, Identification) 
1. ABAS-3 Parent/Primary 
Caregiver Form (Ages 0-
5) 
2. BASC-3 Parent Rating 
Scales-Preschool (Ages 
2-5) 
3. BRIEF- Preschool 
Version 
4. PedsQL Generic Version 
– Parent Report for 
Toddlers (Ages 2-4) 
5. PedsQL 
Multidimensional Fatigue 
– Parent Report for 
Toddlers (Ages 2-4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
~ 10 
minutes 
 
 
 
 
 
 
 
 
 
 
5:0 – 5:11 
1. Cogstate  
(Detection, Identification) 
1. ABAS-3 Parent/Primary 
Caregiver Form (Ages 0-
5) 
2. BASC-3 Parent Rating 
Scales-Preschool (Ages 
2-5) 
3. BRIEF- Preschool 
Version 
4. PedsQL Generic Version 
– Parent Report for 
Young Children (Ages 5-
7) 
5. PedsQL 
Multidimensional Fatigue 
– Parent Report for 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
134 
 
 
Young Children (Ages 5-
7) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
~ 30-40 
minutes 
 
 
 
 
 
 
 
 
6:0 – 6:11 
1. Cogstate  
(Detection, Identification, One 
Card Learning, One Back, Groton 
Maze Learning Task) 
 
 
1. ABAS-3 Parent Form 
(Ages 5-21) 
2. BASC-3 Parent Rating 
Scales-Child (Ages 6-11) 
3. BRIEF 
4. PedsQL Generic Version 
– Parent Report for 
Young Children (Ages 5-
7) 
5. PedsQL 
Multidimensional Fatigue 
– Parent Report for 
Young Children (Ages 5-
7) 
 
~ 50 minutes 
7:0-7:11 
1. Cogstate  
(Detection, Identification, One 
Card Learning, One Back, Groton 
Maze Learning Task) 
1. ABAS-3 Parent Form 
(Ages 5-21) 
2. BASC-3 Parent Rating 
Scales-Child (Ages 6-11) 
3. BRIEF 
4. PedsQL Generic Version 
– Parent Report for 
Young Children (Ages 5-
7) 
5. PedsQL 
Multidimensional Fatigue 
– Parent Report for 
Young Children (Ages 5-
7) 
6. CSSRS – Children’s 
Version 
~ 50 – 55  
minutes 
8:0-9:11 
1. Cogstate  
(Detection, Identification, One 
Card Learning, One Back, Groton 
Maze Learning Task) 
1. ABAS-3 Parent Form 
(Ages 5-21) 
2.  BASC-3 Parent Rating 
Scales-Child (Ages 6-11) 
3. BRIEF 
4. PedsQL Generic Version 
– Parent Report for 
Children (Ages 8-12) 
5. PedsQL 
Multidimensional Fatigue 
– Parent Report for 
Children (Ages 8-12) 
6. CSSRS – Children’s 
Version 
10:0-11:11 
1. Cogstate  
(International Shopping List, 
Detection, Identification, One 
Card Learning, One Back, Groton 
Maze Learning Task, International 
Shopping List Delayed) 
 
1. ABAS-3 Parent Form 
(Ages 5-21) 
2. BASC-3 Parent Rating 
Scales-Child (Ages 6-11) 
3. BRIEF 
4. PedsQL Generic Version 
– Parent Report for 
Children (Ages 8-12) 
5. PedsQL 
Multidimensional Fatigue 
– Parent Report for 
Children (Ages 8-12) 
6. CSSRS – Children’s 
Version 
 
 
 
 
 
 
 
~ 35-45 
minutes 
 
12:0 – 
12:11 
1. Cogstate  
1. ABAS-3 Parent Form 
(Ages 5-21) 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
135 
 
 
(International Shopping List, 
Detection, Identification, One 
Card Learning, One Back, Groton 
Maze Learning Task, International 
Shopping List Delayed) 
 
2. BASC-3 Parent Ratings 
Scales – Adolescent 
(Ages 12-21) 
3. BRIEF 
4. PedsQL Generic Version 
– Parent Report for 
Children (Ages 8-12) 
5. PedsQL 
Multidimensional Fatigue 
– Parent Report for 
Children (Ages 8-12) 
6. CSSRS 
 
 
 
 
 
 
 
 
 
 
 
~ 50-55  
minutes 
 
 
 
 
 
 
 
 
 
 
 
~ 35-45 
minutes 
 
13:0 – 
17:11 
1. Cogstate  
(International Shopping List, 
Detection, Identification, One 
Card Learning, One Back, Groton 
Maze Learning Task, International 
Shopping List Delayed) 
 
1. ABAS-3 Parent Form 
(Ages 5-21) 
2. BASC-3 Parent Ratings 
Scales – Adolescent 
(Ages 12-21) 
3. BRIEF 
4. PedsQL Generic Version 
– Parent Report for 
Teens (Ages 13-18) 
5. PedsQL 
Multidimensional Fatigue 
– Parent Report for 
Teens (Ages 13-18) 
6. CSSRS 
18:0 – 
25:11 
1. Cogstate  
(International Shopping List, 
Detection, Identification, One 
Card Learning, One Back, Groton 
Maze Learning Task, International 
Shopping List Delayed) 
 
2. ABAS-3 Adult Self-Report Form 
(Ages 16-89) 
3. BASC-3 Self-Report College 
(Ages 18-25) 
4. BRIEF - Adult Self Report 
5. PedsQL Generic Version - Young 
Adult Report (Ages 18-25) 
6. PedsQL Multidimensional Fatigue 
-  Young Adult Report (Ages 18-
25) 
7. BDI-II 
8. CSSRS 
No Parent Reports 
N/A 
~80-90 
minutes 
≥26:0 
1. Cogstate  
(International Shopping List, 
Detection, Identification, One 
Card Learning, One Back, Groton 
Maze Learning Task, International 
Shopping List Delayed) 
2. ABAS-3 Adult Self-Report Form 
(Ages 16-89) 
3. BRIEF - Adult Self Report 
4. PedsQL Generic Version - Adult 
Report (Ages ≥26) 
5. PedsQL Multidimensional Fatigue 
- Adult Report (Ages ≥26) 
6. BDI-II 
7. CSSRS 
 
 

 
 
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APPENDIX V: SAMPLE TEMPLATE OF NEUROPSYCHOLOGICAL STATUS REPORT 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
137 
 
 
APPENDIX VI: DOSE ESCALATION AND EXPANSION COHORT (A1 & B1) SAMPLE CONSENT 
 
NANT 2015-02:  PHASE 1 STUDY OF LORLATINIB (PF-06463922), AN ORAL SMALL MOLECULE 
INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY 
NEUROBLASTOMA 
 
PHASE 1 DOSE ESCALATION & EXPANSION COHORT (A1 & B1): FOR PATIENTS ONE YEAR OF 
AGE UP TO 18 YEARS OF AGE  
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol. 
 
The word “you” used throughout this document refers to you or your child. 
 
WHAT IS THIS STUDY ABOUT? 
This study is a clinical trial, a type of research study. Clinical trials include only patients who choose to take 
part. Please take your time to make your decision about participating. You may discuss your decision with 
your friends, family, and health care team. If you have any questions, you may ask your doctor. 
 
You are being asked to participate in this study because you have a kind of cancer called neuroblastoma. 
It may be that your cancer went away for a while but has grown back (relapsed) or it may be that it has 
never gone away (persistent or resistant tumor) after standard treatment. Standard treatment may have 
included chemotherapy, surgery, radiation therapy, high-dose chemotherapy with a stem cell transplant 
and/or immunotherapy. 
 
WHY IS THIS STUDY BEING DONE? 
 
The purposes of this study are: 
 
• 
To find the highest safe dose of lorlatinib that can be given to children and adolescents with 
refractory or relapsed neuroblastoma without causing severe side effects. 
 
• 
To learn about the side effects of the drug  lorlatinib given at different dose levels to children and 
adolescents 1-18 years of age. 
 
• 
To determine if your tumor gets smaller after treatment with lorlatinib. 
 
• 
To measure the levels of lorlatinib in the blood at different dose levels. 
 
• 
To look at genetic changes in tumor DNA found in the blood during treatment with lorlatinib. 
 
• 
To look at genetic changes in tumor tissue to see if they affect response to lorlatinib. 
 
• 
To describe the amount of neuroblastoma tumor found in the blood and bone marrow by testing 
samples with a new test (called NB5 assay). 
 
The research is being done because: 
Currently there is no known effective treatment for your type of cancer.  We are testing new experimental 
drugs such as lorlatinib in the hopes of finding a drug that may be effective against neuroblastoma tumors 
that have come back (relapsed) or that have never gone away (persistent/refractory) after treatment with 
standard therapy.  
 
This study involves the use of an experimental drug called lorlatinib.  In laboratory testing, lorlatinib blocks the 
Anaplastic Lymphoma Kinase (ALK). ALK may be important in the growth of certain types of cancer cells, 
such as neuroblastoma.  Lorlatinib is considered experimental because it has not been proven to work in a 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
138 
 
 
situation like yours.  Lorlatinib has been approved by the United States Food and Drug Administration (FDA) 
to treat adults with non-small cell lung cancer, a different cancer than yours. It is not approved for 
neuroblastoma.  Lorlatinib has been used only in a small number of adults so there is a lot we do not know 
about it yet.  Lorlatinib has not previously been used in children and adolescents not enrolled on this study.  
This study is called a phase 1 study because the goal is to find the highest dose of lorlatinib that we can 
give safely.  Once we have found out the highest dose of lorlatinib that can be given safely, we will treat 
more children and adolescents with neuroblastoma with this Lorlatinib dose.   
 
All patients enrolled on this phase 1 study have been previously tested and are known to have a defect in 
the ALK gene in their tumor before they start treatment.  You or your doctor should have the results of this 
test before enrolling on this study.     
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
There will be about 60-75 patients enrolling on the 4 study cohorts. You have been given this consent 
because the planned enrollment is on cohort A1 or B1.     When you join the study, you will be assigned a 
certain lorlatinib dose.  This study will test up to five lorlatinib doses in groups of 3-6 patients.  The starting 
lorlatinib dose for the first group of patients was about 25% lower than what was given to adults who 
received lorlatinib without bad side effects.  If this is tolerated without serious side effects, then the lorlatinib 
dose will be increased in groups of 3-6 patients until the fifth dose level or if serious side effects are seen.  
At that point, investigators will have found the highest dose of lorlatinib that can be given without bad side 
effects.  This part of the trial is called cohort A1. 
 
  
Once the maximum tolerated dose is determined, another group of 6 patients will be enrolled and treated 
at this dose of lorlatinib, known as the dose expansion part of the study (Cohort B1).  The purpose of the 
dose expansion part of the study is to gather more information about side effects seen in patients treated 
at the maximum tolerated dose of lorlatinib. The dose expansion cohort (Cohort B1) will not enroll patients 
until the dose escalation part of the study (Cohort A1) is completed and the highest dose of lorlatinib that 
can be given safely without serious side effects is found. 
 
WHAT WILL HAPPEN TO ME IF I TAKE PART IN THIS STUDY? 
 
Before You Begin the Study  
Your doctor will have previously sent your tumor for genetic testing and these results showed your tumor 
has a defect in the ALK gene which allows you to be considered for participation in this study (Cohorts A1 
and B1). 
 
You will need to have the following exams, tests or procedures to find out if you can take part in the study. 
Most of these exams, tests or procedures are part of regular cancer care and may be done even if you do 
not join the study. These tests will also be done at various times throughout the study and at the end of the 
study.  The purpose of these tests is to see how well the treatment works and to measure the status of your 
neuroblastoma.   If you have had some of them recently, they may not need to be repeated. This will be up 
to your doctor. 
 
A medical history & physical exam 
Bone marrow tests3 to check your tumor 
Blood tests1 
Various scans4 to check your tumor 
Pregnancy test (urine or blood)2 
Electrocardiogram (EKG) to check the heart rhythm5 
 
Neuropsychological testing6 
1Some blood tests (cholesterol and fat digestion [triglycerides]) may need to be done on an empty stomach, 
so you cannot eat or drink anything other than water for 8 hours before these tests are done (called fasting).   
Your doctor or nurse will tell you if it is necessary for you to fast before these blood tests are done. 
 
 

 
 
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2If you are a female at least 10 years old or who could have children, you will have a pregnancy test done 
by the doctor the week before starting treatment and then before each cycle of treatment begins.  Both you 
and your parent/legal guardian will be informed of a positive pregnancy test. All men and women who could 
have children must either agree to practice abstinence from heterosexual intercourse or use two effective 
methods of birth control for as long as they participate in this study.  
 
3Bone marrow tests are done by inserting a needle into the hip bone to remove the marrow which is inside 
the bone. 
 
4Various scans are done for diagnosis and checking the response of the tumor to treatment. These may 
include CT and /or MRI scans and MIBG or PET scans. We will recommend scans specific for your case 
and we will answer your questions about these scans. 
 
5Electrocardiogram (EKG) to document your heart rhythm before beginning lorlatinib treatment.  
 
6 Central nervous system effects (speech, memory and mood changes) were seen in previous studies 
treating adults with lorlatinib. Neuropsychological testing will be done within one week of starting treatment 
and at different times during this study to monitor for any changes in thinking skills, behavior and mood.   
Please see the section on Neuropsychological testing below in “During the Study” for more details on what 
tests are done and when they are done during this study. 
 
During the Study   
If the exams, tests and procedures show that you can be in the study, and you choose to take part, lorlatinib 
will be given for 28 days.  This entire period is called a cycle with each treatment cycle being 28 days long.  
You may continue to take lorlatinib for an unlimited number of cycles unless you develop serious side effects 
or your tumor worsens. 
 
Lorlatinib will be given by mouth once a day followed by a small glass of water.  If you vomit lorlatinib within 
20 minutes of taking the dose for the day, that dose can be repeated.  This is the only time a dose of 
lorlatinib can be repeated.  
 
Lorlatinib will be available as a tablet. If you are unable to swallow the tablets whole, you will be instructed 
on how to make a liquid lorlatinib solution at home by mixing the lorlatinib tablets with water and a flavoring 
agent (Ora-Plus®).  Your nurse or doctor will help you decide what is best for you and will make sure you 
have the proper directions for taking this medication. 
 
You will be given a patient diary at the beginning of each cycle of lorlatinib.  Use the diary to record the date 
and time you take the drug, all vomited and missed doses, side effects that you experience and any other 
medications and supplements you are taking.  The diary should be returned to clinic along with the 
medication bottle (even if it is empty) weekly during cycle 1 and then after each treatment cycle of lorlatinib.  
This will help us to know how much of the drug you take and how it made you feel. 
 
During the study you will have tests and procedures done to check for side effects from taking lorlatinib and 
to see how your tumor is doing.  Many of these tests are part of regular cancer care but you may have them 
done more often because you are on the study: 
One Treatment Cycle   
(Cohort A1: dose escalation group and Cohort B1: dose expansion group) 
Week 1 
Week 2 
Week 3 
Week 4 
Days 1 – 7 
Days 8 - 14 
Days 15 - 21 
Days 22 - 28 
 
Lorlatinib once a day 
 

 
 
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Physical exam 
Electrocardiogram (EKG) to test heart rhythm 3 
Blood tests 1 
Bone marrow tests & various scans (CT/MRI, MIBG or PET) to 
check your tumor 4 
Pregnancy test (urine or blood) 2 
 Neuropsychological testing5 
 
1 Some blood tests (cholesterol and fat digestion) may be done on an empty stomach, so patients cannot 
eat or drink anything other than water for 8-10 hours before these tests are done.   
 
2 A urine or blood pregnancy test will be done before each treatment cycle begins if you are a female at 
least 10 years old or who could have children.  Both you and your parent/legal guardian will be informed of 
a positive pregnancy test.  All men and women who could have children must continue to practice 
abstinence from heterosexual intercourse or use two effective methods of birth control for as long as they 
participate in this study.  
3 Electrocardiogram (EKG) done before starting study treatment will be repeated at certain times during the 
study to document if lorlatinib treatment has any effect on heart rhythm. 
 
4 Bone marrow tests and various scans are done for checking the response of your tumor to treatment.  
These tests will be done at certain times during the study to look at response to lorlatinib and check that 
your tumor has not gotten worse. 
 
5 Neuropsychological Testing 
Neuropsychological evaluations try to understand how changes in the health of the brain may affect 
behavior or mood and how well a person is able to pay attention, remember things or solve problems.  Since 
effects on speech, memory and mood were seen in a small number of adults receiving lorlatinib, 
neuropsychological testing will be done to monitor for changes in thinking skills, behavior and mood at 
different times during this study.  A table at the end of the consent lists how often neuropsychological testing 
will be done during the study.  Testing methods are based on the age of the patient and include 
computerized tests using an iPad, written questionnaires and evaluations by a licensed psychologist.  
Parents or legal guardians of patients less than 18 years of age will also participate by completing written 
questionnaires at the same time their child is being tested.   
 
If the testing results show areas of concern, you may be given more frequent testing as well as referrals for 
other care if needed.  During testing, patients may skip questions that are stressful and may stop taking the 
tests at any time.  Testing can be done as part of the clinic visit.  You will need to talk with your doctor and 
nurse about scheduling to do these tests at times that are workable for you and your child. 
 
• 
All patients 3 years of age and older will do computerized tests using an iPad.  While the patient is 
taking these tests, the patient’s parent or legal guardian will complete written questionnaires about 
the patient’s mood and emotions, behavior, daily living/functional skills and social skills with others.  
The parent/legal guardian can be in the same room during the testing but they cannot help their 
child with their tests.   
• 
Patients 18 years of age will complete computerized tests using an iPad and their own written 
questionnaires.  Parents/Legal guardians do not have testing to do with patients of this age. 
• 
Patients under 3 years of age will have an evaluation of overall functioning including language, 
motor and cognitive development done by a licensed psychologist.  This testing will take 60 to 90 
minutes to complete.  Parents/legal guardians will also complete written questionnaires at the same 
time. 
 
 
 

 
 
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Patient age at 
testing in years 
Testing being done 
Length of testing time  
for Patients 
Length of testing time for 
Parents/legal guardians 
1 
Patient: licensed psychologist 
Parent/legal guardian: written 
questionnaires 
~ 60 - 90 minutes 
~ 20 minutes 
2 
~ 50 minutes 
3 - 5 
Patient: computerized tests using an 
iPad 
Parent/legal guardian: written 
questionnaires 
~ 10 minutes 
~ 50 minutes 
6 
~ 30 – 40 minutes 
~ 50 minutes 
7 - 9 
~ 30 – 40 minutes 
~ 50 - 55 minutes 
10 - 17 
~ 35 – 45 minutes 
~ 50 - 55 minutes 
18 
Patient: computerized tests using an 
iPad and written questionnaires 
~ 80 – 90 minutes 
NA 
 
NANT Biology Study (NANT 2004-05) 
If you choose to participate in this research, you will also be asked to join a companion NANT biology study 
to collect blood, bone marrow and tumor tissue (if available) and reports from radiology scans from patients 
with neuroblastoma. The biology study also provides a place (called NANT biorepository) where any leftover 
samples of tumor tissue or bone marrow and blood collected on this study could be transferred and stored. 
While you will be asked to join the Biology Study (NANT 2004-05), the decision to store/bank any leftover 
samples is optional and will not affect your ability to participate in this treatment study with Lorlatinib.  Your 
doctor will talk with you in detail about the NANT biology study and have you sign a separate consent form. 
 
Additional Tests in this Study 
We would like to do some extra tests called pharmacokinetic studies and biologic studies.  These tests will 
help us learn more about lorlatinib and may help children and adolescents 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 meaning you can decide whether you 
want to do them or not.  
 
Pharmacokinetic Studies: Determining Blood Levels of Lorlatinib – Required  
During this study blood samples will be collected to determine how much lorlatinib is in your blood (called 
pharmacokinetics). About 3mL (just over half a teaspoon) of blood will be drawn with each sample.  A total of 
9 blood samples will be obtained over 3 separate days during course 1 (Day 1, Day 2 and Day 15).  The total 
amount of blood drawn for testing will be about 27 mL (almost 5 ½ teaspoons). If you have a central line (such 
as a port or a Broviac) these samples can be drawn through that line or through a small tube placed in a vein 
in your hand or arm.  This amount of blood is considered safe to donate. Samples will be sent to a commercial 
laboratory contracted to perform these tests for the study. These samples will be the property of Pfizer and 
Pfizer may also use the PK Biological Samples for evaluation of the bioanalytical method. 
 
Other Biology Research Tests in this Study - Optional 
You will be asked if you want to participate in 3 optional research tests.  You can decide not to let the doctors 
do these tests and still be able to be treated as part of this study.  There are checkboxes at end of this form 
to mark whether you are willing to participate in these voluntary studies. The results of these research tests 
will not be shared with you or become part of your medical record.  These results would also not be used to 
make decisions about your care while enrolled on this study.     
 
 
 
 
 
 

 
 
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• 
Using extra blood to look for genetic changes seen in tumor cells. 
Tumor cells often release small pieces of DNA into the blood stream where it can be detected by 
sensitive tests.  For this study, researchers would like to take almost 4 additional teaspoons of blood 
(17mL) at study entry and at each time a disease evaluation is done (after cycle 2, 4, 6 and then 
every 4th cycle after that) to look at what genetic changes in your tumor can be seen in your blood 
over time. The blood will be sent to a commercial laboratory for genetic testing.    
 
• 
Comparing genetic changes between leftover tumor from a surgical procedure prior to tumor 
relapse (at diagnosis or when you had surgery done after diagnosis) to relapsed 
neuroblastoma tumor tissue and bone marrow aspirates and whether these changes affect 
how the tumor will respond to treatment with Lorlatinib. 
 Researchers would like to look at tumor tissue to determine if there are certain gene changes  
 present that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.   
 These tests would be done on tumor tissue remaining from diagnosis, or any previous surgery  
 where tumor tissue was removed (removal of primary tumor or removal of tumor at a relapse) in  
the past. The tissue and bone marrow aspirates will be sent to a research laboratory at Children’s 
Hospital of Philadelphia for testing.   
 
When You Have Finished Treatment with Lorlatinib  
After you stop treatment on this study, you will continue to have tests and scans done (listed below) to 
measure how much tumor is left. If test results show you have abnormal organ function, tests are 
recommended by the study to be repeated monthly until test results are stable or normal. You doctor will 
tell you how often these tests and evaluations will be done. 
 
Medical Tests after the Study: 
 
Physical exam  
Neuropsychological testing1 
Blood tests 
Bone marrow tests & various scans to check your tumor2 
Electrocardiogram 
(EKG) 
to 
check the heart rhythm3 
 
 
1The same neuropsychological testing and evaluation done before starting study treatment will be done at 
the end of treatment with lorlatinib.  The need for any further testing after this will be up to your doctor. 
 
2Bone marrow tests and various scans (CT/MRI, MIBG or PET) are done for checking the response of your 
tumor to treatment.  These tests will be done at the end of a course and at certain times following treatment 
to monitor your tumor status. 
 
3 Electrocardiogram (EKG) done at the end of the study to document if lorlatinib treatment has any effect 
on heart rhythm.  
 
A table detailing the tests and procedures required before, during and after the study has been attached to 
the end of this consent (Consent Addendum 1). 
 
HOW LONG WILL I BE ON THIS STUDY?  
You can get an unlimited number of treatment cycles with lorlatinib as long as you are not having bad side 
effects and as long as your tumor is not getting worse.   
 
After you stop treatment, you will continue to have tests and scans done to measure how much tumor is left. 
Your doctor will tell you how often these tests will be done. Researchers will continue to collect information 
about you for a lifetime. Information will be collected about whether you are still alive; whether your tumor has 
grown back and at what sites in the body; whether you have developed any side effects from the treatment; 

 
 
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or whether you have developed any additional cancer. Your doctor will give the researchers this information 
at regular intervals. 
 
CAN I STOP BEING IN THE STUDY? 
Yes. If you are thinking about stopping your participation on this study, you should talk to your doctor before 
making a final decision so he/she can tell you how to do this safely.  
 
Your doctor may also stop you from taking part in this study at any time if he/she believes it is in your best 
interest; if you do not follow study rules; or if the study is stopped. 
 
WHAT ARE THE RISKS OF THE STUDY? 
This is a Phase 1 study.  A Phase 1 study looks at how common and serious side effects can be for each 
patient at a specific dose of a drug. In a Phase 1 study, some patients may have very serious side effects 
and could die as a result of these side effects. You may be one of those patients who have serious side 
effects as a result of participating in this Phase 1 study.  
 
In this study, researchers will be looking at side effects seen in patients taking different doses of lorlatinib. 
Since subjects will be assigned to different dose levels of lorlatinib, some subjects may receive doses that 
are too small to be effective while others may receive higher doses that may cause increased side effects.  
 
Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know 
all the side effects that may happen. Side effects may be mild or very serious. Other drugs may be given 
to make side effects less serious and more comfortable (such as for nausea, headache or reaction to 
lorlatinib). Many side effects go away soon after you stop taking the study medications but it is always 
possible that side effects can be serious, long lasting or may never go away. There is also a risk of death. 
Patients are watched carefully and treatment will be stopped if bad side effects develop. There may also 
be risks we do not know about. You should talk to your doctor about any side effects that you have while 
taking part in this study.  
 

 
 
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While on the study, you are at risk for the side effects listed below: 
 
Possible Risks of Lorlatinib 
 
The following side effects are considered to be related to lorlatinib have been reported:  
Very Common  
(may affect 10 or more in 100 people) 
Common 
(may affect from 1 up to less than 10 in 100 people) 
• 
Increase in cholesterol and triglycerides 
(fats in your blood)  
• 
Effects on mood (for example, irritability 
and mood swings)  
• 
Effects on memory (for example, 
confusion, memory loss and disturbance 
of attention)  
• 
Effects on the peripheral nerves which are 
those outside of the brain and spinal cord, 
including tingling, numbness or pain in 
hands and feet)  
• 
Changes in vision (including double 
vision, perceived flashes or floaters of 
light, light intolerance, vision blurred, 
vision sharpness reduced and visual 
impairment) 
• 
Hypertension  
• 
Diarrhea  
• 
Constipation  
• 
Joint pain  
• 
Build-up of fluid in the body or extremities 
causing swelling (edema)  
• 
Fatigue (feeling tired and exhausted)  
• 
Increase in body weight 
• 
Increase in blood sugar levels 
• 
Hallucination and loss of contact with 
reality 
• 
Changes in mental status  
• 
Changes in speech (for example, slow 
speech or slurred speech) 
• 
Inflammation of the lungs (pneumonitis) 
which can cause shortness of breath and 
difficulty breathing. If severe, this can be 
life threatening.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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The following events have also been reported in patients while they were taking lorlatinib, although the 
relationship to lorlatinib is uncertain:  
 
Very common (may affect 10 or more in 100 people) 
• 
Abnormalities in blood tests that may indicate liver damage 
• 
Abnormal pancreas tests 
• 
Decrease in hemoglobin in the blood that can cause weakness 
• 
Headache 
• 
Muscle pain 
• 
Difficulty sleeping 
• 
Rash 
 
Common (may affect from 1 up to less than 10 in 100 people) 
• 
Decrease of ejection fraction of the heart which may indicate severe heart problem 
• 
A sudden and temporary loss of consciousness (syncope) 
• 
Changes in the electrical activity of your heart that might lead to a heart rhythm problem and/or 
irregular heartbeat 
 
Uncommon (may affect less than 1 in 100 people) 
• 
Inflammation of the pancreas causing pain in the upper abdomen. This could become severe and 
may cause nausea and vomiting, fever and rapid heart rate. This could require hospitalization and 
may be life threatening 
• 
Suicidal thoughts  
• 
Psychosis 
 
Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised 
when driving or operating machines as patients may experience CNS effects.  
 
Possible Risks to Unborn Child 
 
Patients who agree to participate in this study should not become pregnant while on this study. Lorlatinib 
may cause fetal harm when administered to a pregnant woman and is not recommended during 
pregnancy or for women of childbearing potential not using contraception. Women of childbearing 
potential should use nonhormonal methods of birth control. If a hormonal method of birth control is 
unavoidable, then a condom must be used in combination with the hormonal method. Female patients 
must continue to follow these birth control guidelines for 21 days after finishing the study. Male patients 
must wear condoms as one of their forms of birth control for the duration of the study and for 97 days 
after finishing the study. Further contraception use should be discussed with your personal physician. If 
you or your partner becomes pregnant while you are participating in this study, please notify your doctor 
immediately.  For more information about risks and side effects, ask your doctor. 
 
Possible Long Term Side Effects of Treatment with Lorlatinib 
Side effects in adults treated with lorlatinib have occurred while patients have been receiving the drug or 
shortly after finishing the drug.  It is not known if some side effects may be seen only after a long time after 
finishing treatment with lorlatinib.   
 
Possible Risks from Having Blood Drawn 
The risks from having your blood taken are minimal, but can include an infection or a blood clot. Experienced 
doctors or nurses will perform these blood draws to minimize this risk.   
 
 
 

 
 
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Unknown Risks 
The treatment may have side effects that no one knows about yet.  The researchers will let you know if they 
learn anything that might make you change your mind about participating in the study. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
There may or may not be direct medical benefit to you. The information learned from this study may or may 
not benefit other children or young people with solid cancers in the future. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
There are other options for you instead of this treatment. Instead of being in this study, you have these 
options: 
• 
Treatment with other chemotherapy medicines  
• 
Treatment with other experimental agents that may be available 
• 
No neuroblastoma therapy at this time, with care to help you feel more comfortable 
Please talk about these options with your doctor. 
 
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. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance and data 
analysis include: 
• 
New Approaches to Neuroblastoma Therapy (NANT) Consortium at Children’s Hospital Los 
Angeles in Los Angeles, CA.  The NANT Consortium identifies you by a number. 
• 
Independent auditor evaluating quality assurance for the NANT Consortium. 
• 
The National Cancer Institute (NCI) and other governmental agencies, like the Food and Drug 
Administration (FDA), Health Canada, or European regulatory agency(ies) involved in keeping 
research safe for people. 
• 
Foundation Medicine, Inc. who is a collaborator on this study.  
• 
Pfizer Inc., the pharmaceutical company which makes lorlatinib. 
 
NANT has received a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects. Information about the certificate is included at the end 
of this consent. 
 
Because this study involves the treatment of a medical condition, a copy of this consent form will be placed 
in your medical record. This will allow the doctors that are caring for you to obtain information about what 
medications or procedures you are receiving in the study and treat you appropriately. 
 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
Taking part in this study may lead to added costs to your insurance company.  Your health insurance 
company will be billed for many expenses associated with the costs of this study.  These expenses include 
medications, treatments, hospital charges, and doctors’ fees related to your participation in this study.   
 
Lorlatinib and the flavoring agent (Ora-Plus®) are being provided free of charge for use in this study, but 
the costs associated with administering the drug is normally covered by your insurance company.  The cost 
of doing a heart test called an EKG and neuropsychological testing at several time points during your 
participation in the study with lorlatinib is being done as part of research and will be paid for by the study.  
The special research blood and tissue studies will be done at no cost to you.  However, you or your health 
plan may need to pay for the costs of the supplies and personnel who draw the blood from you for these 
tests. 
  

 
 
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You may have to pay for other things during this study, such as but not limited to, your time, the cost of 
food you buy while you are being treated at the hospital, car fare, travel to and from the hospital for 
treatment, parking, and baby sitter fees. 
Taking part in this study may lead to added costs that may not be covered by your insurance company. 
Please ask about any expected added costs or insurance problems. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
website at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .   You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this website. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)] if you feel that 
you have been injured because of taking part in this study. You can tell the doctor in person or call him/her 
at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study. You and/or your 
health plan will be charged for this treatment.  The study will not pay for medical treatment.  
 
WHAT ARE MY RIGHTS AS A STUDY PARTICIPANT? 
Taking part in this study is your choice. You may choose not to take part or not take part in the study. If you 
decide to take part in this study, you may remove yourself from 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. If you 
remove yourself from the study, we will still take care of you. We will explain what stopping the treatment 
may do and we will offer other treatments if they are available.  
 
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 case of injury resulting from this study, you do not lose any of you legal rights to seek payment by signing 
this form. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing data from this 
research throughout the study.  We will tell you about new information from this Board or other studies that 
may affect your health or willingness to stay in the study. 
 
 
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).  
 
WHO IS FUNDING THIS RESEARCH STUDY? 
This study is supported by Pfizer, Inc. Pfizer is a drug company that makes the drug being studied in this 
research project. Pfizer is giving money to Children's Hospital for some of the costs of the study. The results 
of the study will be reported to Pfizer. If the study shows that lorlatinib may be useful for a new purpose, 
this could benefit Pfizer financially. 
 
 

 
 
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The Children’s Hospital Los Angeles/NANT is also providing funding for this study. 
 
Dr. Mossé at Children’s Hospital of Philadelphia, one of the principal investigators of this study, has served 
as a paid consultant to Pfizer. Her participation in this research has been reviewed and approved, subject 
to management, according to CHOP’s/NANT Conflict of Interest Policy.  
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the NCI’s Cancer Information Service at 
 
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615 
 
You may visit the NCI Web sites 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/ 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  
This website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this website at any time. 
 
You will get a copy of this consent form. If you want more information about this study, ask your doctor. 
 
 

 
 
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CONSENT FOR EXTRA STUDIES FOR RESEARCH  
 
The following tests are optional for all patients in the study. You may still participate in the study 
even if you do not agree to these tests. 
 
1. Using extra blood to look for genetic changes seen in tumor cells 
 
Initial next to YES if you agree to let researchers take almost 4 extra teaspoons (17mL) at study entry 
and each time a disease evaluation is done)  to look at what genetic changes in your tumor can be seen 
in your blood over time before and after treatment with lorlatinib.  This blood would be drawn at a time 
when blood was being drawn for clinical purposes.  The blood will be sent to Foundation Medicine Inc. 
for analysis who is a collaborator on the study. The results of these tests will be confidential and not 
made available to you or your treating physician. 
 
Initial next to NO, if you do not want researchers to take extra blood above what is needed for clinical 
purposes. 
 
_______Yes       
_______No    
 
2. Comparing genetic changes between tumor leftover from a surgical procedure prior to relapse 
(diagnosis or second look) to relapsed neuroblastoma tumor tissue and bone marrow aspirates 
and whether these changes affect how the tumor will respond to treatment with lorlatinib. 
 
Initial next to YES, if you agree (and if there is tumor remaining)  to let this tumor be sent to a laboratory 
so researchers can compare these samples and determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  The results of 
these tests will be confidential and not made available to you or your treating doctor. 
 
Initial next to NO if you do not want leftover tumor from an earlier procedure to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely to 
respond to the drug lorlatinib. 
 
_______Yes      _______No   
 
 
Initial next to YES, if you agree to let extra bone marrow aspirates be collected to be sent to a laboratory 
so researchers can compare these samples and determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  The results of 
these tests will be confidential and not made available to you or your treating doctor. 
 
Initial next to NO if you do not want these bone marrow aspirates collected to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely to 
respond to the drug lorlatinib. 
 
_______Yes      _______No   
 

 
 
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STATEMENT OF CONSENT 
 
I have already read the information in this informed consent document. I have read all the attachments that 
were included with this informed consent document. I have asked all of my questions and I have gotten 
answers. I agree to enroll myself (my child) in this study. 
 
 
_____________________________________ 
Print Patient Name 
 
 
______________________________________  
 
_____/_____/_____ 
Print Name of Parent or Guardian  
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Parent or Guardian  
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Patient (If > 7 years old) 
 
 
 
 
Date 
 
 
___________________________________________ 
 
_____/_____/______ 
Signature of Physician or  
 
 
 
 
 
Date 
Responsible Investigator 
 
_______________________________________ 
 
____/_____/______ 
Signature of Witness 
 
 
 
 
 
 
Date 
 
 
_______________________________________ 
 
____/_____/______ 
Signature of Translator  
 
 
 
 
 
Date 
 
 

 
 
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Consent Addendum I: Tests That Will Be Done On This Study 
Observation 
Before Entry 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of 
Therapy 
Physical exam including 
neurological exam 
X 
Weekly 
Start of cycle 
Start of each cycle 
X 
Routine Blood tests** 
(Blood counts, 
electrolytes, liver, kidney 
function, function of 
pancreas- amylase/lipase) 
X 
Weekly 
Weekly for blood counts and 
twice during cycle for all 
other blood tests   
Start of each cycle 
X 
Routine Blood tests** 
(Fasting cholesterol, 
triglycerides, glucose) 
X 
Every other 
week  
Start of cycle  
Start of each cycle  
X 
Hemoglobin A1c (HbA1c)  
X  
 
Start of cycle  
With Disease 
Evaluations in 
Courses 4 and 6 
and after every 4 
courses thereafter  
X 
Pregnancy test 
(All females 10 years of 
age and older) 
X 
 
Start of cycle 
Start of each cycle 
 
Heart rhythm test 
(EKG)  
X 
One hour after 
day 1 treatment 
is finished 
End of cycle 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
Neuropsychological 
Testing  
Within one 
week before 
starting 
treatment 
End of cycle 
End of cycle 
 End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
Neuropsychological 
evaluation with licensed 
psychologist for patients 
less than 3 years of age 
Within one 
week before 
and up to two 
weeks after 
starting 
treatment 
 
End of cycle 
End of cycle 6, 10 
and then every 8 
cycles thereafter  
X 
Submit Patient Treatment 
Diaries 
 
X 
X 
X 
X 
Blood for Lorlatinib drug 
level tests (PK - Required) 
 
Day 1: 3 times 
Day 2: 1 time 
Day 15: 5 times 
 
 
 
Blood for circulating tumor 
cells (Optional) 
X 
 
With disease evaluation 
End of cycle (4,6, 
and every 4th cycle 
thereafter) 
 
Bone Marrow Aspirate 
(Optional) 
X 
 
With disease evaluation 
End of cycle (4,6, 
and every 4th cycle 
thereafter) 
 
Sampling of  leftover 
tumor tissue (Optional) 
Leftover tumor tissue can be sent at any time during the study 

 
 
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Tests done during Disease Evaluation  
Bone marrow aspirate and 
biopsy 
X 
 
Week 4 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
CT/MRI scans and/or 
MIBG/PET scans 
Blood and bone marrow 
for NANT Biology study# 
# Patients enrolled in the companion biology study may have additional samples of blood and bone marrow collected at study entry 
and with each disease evaluation time point. Please look at the biology study N04-05 consent form for more information 
**Blood draws can be done more often if needed at the discretion of your study doctor 
 
 

 
 
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Consent Addendum II 
Certificate of Confidentiality Information 
 
NANT 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. 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX VII: LORLATINIB IN COMBINATION WITH CONVENTIONAL CHEMOTHERAPY (COHORT 
B2) SAMPLE CONSENT 
 
NANT 2015-02:  PHASE 1 STUDY OF LORLATINIB, AN ORAL SMALL MOLECULE INHIBITOR OF 
ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY NEUROBLASTOMA 
 
LORLATINIB IN COMBINATION WITH CONVENTIONAL CHEMOTHERAPY (COHORT B2): FOR 
PATIENTS ONE YEAR OF AGE THROUGH 30 YEARS OF AGE 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol. 
 
The word “you” used throughout this document refers to you or your child. 
 
WHAT IS THIS STUDY ABOUT? 
This study is a clinical trial, a type of research study. Clinical trials include only patients who choose to take 
part. Please take your time to make your decision about participating. You may discuss your decision with 
your friends, family, and health care team. If you have any questions, you may ask your doctor. 
 
You are being asked to participate in this study because you have a kind of cancer called neuroblastoma. 
It may be that your cancer went away for a while but has grown back (relapsed) or it may be that it has 
never gone away (persistent or resistant tumor) after standard treatment. Standard treatment may have 
included chemotherapy, surgery, radiation therapy, high-dose chemotherapy with a stem cell transplant 
and/or immunotherapy. 
 
WHY IS THIS STUDY BEING DONE? 
 
The purposes of this study are: 
 
• 
To find the highest safe dose of lorlatinib that can be given to children, adolescents and adults with 
refractory or relapsed neuroblastoma without causing severe side effects. 
 
• 
To learn about the side effects of the drug lorlatinib when given in combination with 
cyclophosphamide and topotecan) in children, adolescents and adults. 
 
• 
To determine if your tumor gets smaller after treatment with lorlatinib when given in combination 
with cyclophosphamide and topotecan. 
 
• 
To measure the levels of lorlatinib in the blood when given together with cyclophosphamide and 
topotecan in children and adolescents. 
 
• 
To look at genetic changes in tumor DNA found in the blood during treatment. 
 
• 
To look at genetic changes in tumor tissue to see if they affect response to lorlatinib. 
 
• 
To describe the amount of neuroblastoma tumor found in the blood and bone marrow by testing 
samples with a new test (called NB5 assay). 
 
The research is being done because: 
Currently there is no known effective treatment for your type of cancer. We are testing new experimental 
drugs such as lorlatinib in the hopes of finding a drug that may be effective against neuroblastoma tumors 
that have come back (relapsed) or that have never gone away (persistent/refractory) after treatment with 
standard therapy. This part of the study will combine three drugs: lorlatinib, cyclophosphamide and 
topotecan.  You may have taken cyclophosphamide and/or topotecan before (but not all three together) for 
treatment of your neuroblastoma. 

 
 
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This study involves the use of an experimental drug called lorlatinib.  In laboratory testing, lorlatinib blocks the 
Anaplastic Lymphoma Kinase (ALK). ALK may be important in the growth of certain types of cancer cells 
such as neuroblastoma. Lorlatinib is considered experimental because it has not been proven to work in a 
situation like yours.  Lorlatinib has been approved by the United States Food and Drug Administration (FDA) 
to treat adults with non-small cell lung cancer, a different cancer than yours. It is not approved for 
neuroblastoma.  Lorlatinib has been used only in a small number of adults so there is a lot we do not know 
about it yet.  Lorlatinib has not previously been used in children and adolescents not enrolled on this study. 
 
Cyclophosphamide and topotecan are chemotherapy drugs that are FDA-approved for the treatment of 
certain adult cancers, but have not been approved to treat children with neuroblastoma. These drugs have 
been used in combination to treat many children with neuroblastoma and in some patients this combination 
has reduced the amount of neuroblastoma present. Even if you have previously received treatment with 
cyclophosphamide and topotecan, you can still participate in this study. 
 
All patients enrolled on this study are known to have a defect in the ALK gene in their tumor before they 
start treatment. You or your doctor should have the results of this test before being able to enroll on this 
study.  
 
A dose of lorlatinib that can be given safely to children and adolescents was chosenfrom the dose escalation 
part of the study.  Lorlatinib has not been given in combination with chemotherapy in patients with childhood 
tumors. In this part of the study, we will test the dose of lorlatinib that can be given safely in combination 
with cyclophosphamide and topotecan to children, adolescents and adults up to age 30 with 
relapsed/refractory neuroblastoma. After 4 cycles of chemotherapy, you and your physician may decide to 
stop the chemotherapy and continue lorlatinib without the chemotherapy.   
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
There will be about 60-75 patients enrolling on the 4 study cohorts.  Of this number, about 12-18 children 
and adolescents and adults up to age 30 will be enrolled on this part of the study where lorlatinib is given 
together with cyclophosphamide and topotecan). 
 
WHAT WILL HAPPEN TO ME IF I TAKE PART IN THIS STUDY? 
 
Before You Begin the Study  
Your doctor will have previously sent your tumor for genetic testing and these results showed your tumor 
has a defect in the ALK gene which allows you to be considered for participation in this study (Cohort B2). 
 
You will need to have the following exams, tests or procedures to find out if you can take part in the study. 
Most of these exams, tests or procedures are part of regular cancer care and may be done even if you do 
not join the study.   
These tests will also be done at various times throughout the study and at the end of the study.  The purpose 
of these tests is to see how well the treatment works and to measure the status of your neuroblastoma.   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 
Bone marrow tests3 to check your tumor 
Blood tests1 
Various scans4 to check your tumor 
Pregnancy test (urine or blood)2 
Electrocardiogram (EKG) to check the heart rhythm5 
 
Neuropsychological testing6 
1Some blood tests (cholesterol and fat digestion [triglycerides]) may need to be done on an empty stomach, 
so you cannot eat or drink anything other than water for 8 hours before these tests are done (called fasting).  
Your doctor or nurse will tell you if it is necessary for you to fast before these blood tests are done. 
 

 
 
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2If you are a female at least 10 years old or who could have children, you will have a pregnancy test done 
by the doctor the week before starting treatment and then before each cycle of treatment begins. Both you 
and your parent/legal guardian (if applicable) will be informed of a positive pregnancy test. All men and 
women who could have children must either agree to practice abstinence from heterosexual intercourse or 
use two effective methods of birth control for as long as they participate in this study.  
 
3Bone marrow tests are done by inserting a needle into the hip bone to remove the marrow which is inside 
the bone. 
 
4Various scans are done for diagnosis and checking the response of the tumor to treatment. These may 
include CT and /or MRI scans and MIBG or PET scans. We will recommend scans specific for your case 
and we will answer your questions about these scans. 
 
5Electrocardiogram (EKG) to document your heart rhythm before beginning lorlatinib treatment.  
 
6Central nervous system effects (speech, memory and mood changes) were seen in previous studies 
treating adults with Lorlatinib.  Neuropsychological testing will be done at within one week of starting 
treatment and at different times during this study to monitor for any changes in thinking skills, behavior and 
mood.   Please see the section on Neuropsychological testing below in “During the Study” for more details 
on what tests are done and when they are done during this study. 
 
During the Study   
If the exams, tests and procedures show that you can be in the study, and you choose to take part, lorlatinib 
will be given once a day for 28 days and will be given together with cyclophosphamide/topotecan on the 
first 5 days.  This entire period is called a cycle with each treatment cycle being 28 days long.  You may 
continue to receive treatment with lorlatinib and cyclophosphamide/topotecan for up to 24 cycles or 
indefinitely if you are no longer receiving chemotherapy unless you develop serious side effects or your 
tumor worsens. 
 
One Treatment Cycle  
Cohort B2:  Lorlatinib with chemotherapy 
Week 1 
Week 2 
Week 3 
Week 4 
 Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Days  
8-14 
Days  
15 -21 
Days 22-28 
 
*Lorlatinib  once a day 
 
CPM 
CPM 
CPM 
CPM 
CPM 
 
 
 
 
 
TOPO 
TOPO 
TOPO 
TOPO 
TOPO 
MGF 
 
 
 
 
 
CPM: Cyclophosphamide 
 
TOPO: Topotecan 
 
MGF:  Myeloid growth factor 
*Lorlatinib should be given at least one hour before chemotherapy on days 1-5 of each cycle.  
 
Lorlatinib 
Lorlatinib will be given by mouth once a day followed by a small glass of water. Lorlatinib should be given 
at least one hour before chemotherapy on days 1 – 5 of each cycle.   If you vomit lorlatinib within 20 minutes 
of taking the dose for the day, that dose can be repeated.  This is the only time a dose of lorlatinib can be 
repeated.  
 
 

 
 
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Lorlatinib will be available as a tablet. If you are unable to swallow the tablets whole, you will be instructed 
on how to make a liquid lorlatinib solution at home by mixing the lorlatinib tablets with water and a flavoring 
agent (Ora-Plus®). Your nurse or doctor will help you decide what is best for you and will make sure you 
have the proper directions for taking this medication. 
 
You will be given a patient diary at the beginning of each cycle of lorlatinib.  Use the diary to record the date 
and time you take the drug, all vomited and missed doses, side effects that you experience and any other 
medications and supplements you are taking.  The diary should be returned to clinic along with the 
medication bottle (even if it is empty) weekly during cycle 1 and then at the end of each treatment cycle.  
This will help us to know how much of the drug you take and how it made you feel. 
 
Cyclophosphamide & Topotecan 
You will receive both cyclophosphamide and topotecan into the bloodstream (either through your central 
line or through a small tube placed in a vein in your hand or arm) on days 1 through 5 of each cycle.  You 
will receive each medicine over 30 minutes and the cyclophosphamide will be given first.  These medicines 
are typically given in the clinic. You may stop cyclophosphamide and topotecan after 4 courses after 
discussion with your physician if it is deemed to be in your interest.    
 
Myeloid Growth Factor 
In addition, you will be given a medicine to help boost your white blood cell count.  White blood cells help 
fight infection and having low white blood cells can increase your risk of developing an infection. This drug 
will be started on day 6 of each treatment cycle if you receive chemotherapy.  Filgrastim or G-CSF is a shot 
given into the skin each day until the white blood cell count increases.  Pegfilgrastim is a long-acting version 
of Filgrastim that is given as shot into the skin just once on day 6 of the cycle.  Your doctor will talk with you 
about which of these study drugs you will receive.  
 
During the study you will have tests and procedures done to check for side effects from taking lorlatinib in 
combination with chemotherapy and to see how your tumor is doing.  Many of these tests are part of regular 
cancer care but you may have them done more often because you are on the study: 
 
Physical exam 
Electrocardiogram (EKG) to test heart rhythm 3 
Blood tests 1 
Bone marrow tests & various scans (CT/MRI, MIBG or PET) to check 
your tumor 4 
Pregnancy test (urine or 
blood) 2 
Neuropsychological testing 5 
 
1 Some blood tests (cholesterol and fat digestion) may be done on an empty stomach, so patients cannot 
eat or drink anything other than water for 8-10 hours before these tests are done.   
 
2 A urine or blood pregnancy test will be done before each treatment cycle begins if you are a female at 
least 10 years old or who could have children.  Both you and your parent/legal guardian will be informed of 
a positive pregnancy test. All men and women who could have children must continue to practice 
abstinence from heterosexual intercourse or use two effective methods of birth control for as long as they 
participate in this study.  
3 Electrocardiogram (EKG) done before starting study treatment will be repeated at certain times during the 
study to document if lorlatinib treatment has any effect on heart rhythm. 
 
4 Bone marrow tests and various scans are done for checking the response of your tumor to treatment.  
These tests will be done at certain times during the study to look at response to lorlatinib and check that 
your tumor has not gotten worse. 
 
 
 

 
 
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5Neuropsychological Testing 
Neuropsychological evaluations try to understand how changes in the health of the brain may affect 
behavior or mood and how well a person is able to pay attention, remember things or solve problems.  Since 
effects on speech, memory and mood were seen in a small number of adults receiving lorlatinib, 
neuropsychological testing will be done to monitor for changes in thinking skills, behavior and mood at 
different times during this study. Testing methods are based on the age of the patient and include 
computerized tests using an iPad, written questionnaires and evaluations by a licensed psychologist.  
Parents or legal guardians of patients less than 18 years of age will also participate by completing written 
questionnaires at the same time their child is being tested.   
 
The results of the neuropsychological testing will be told to your doctor and entered as part of your medical 
record. Neuropsychological results will be used to make decisions about your care while enrolled on this 
study.  If the testing results show areas of concern, you may be given more frequent testing as well as 
referrals for other care if needed.  During testing, patients may skip questions that are stressful and may 
stop taking the tests at any time.  Testing can be done as part of the clinic visit.  You will need to talk with 
your doctor and nurse about scheduling to do these tests at times that are workable for you and your child.  
Please see the table at the end of the consent form that tells how often these tests will be done during the 
study. 
 
• 
All patients 3 years of age and older will do computerized tests using an iPad.  While the patient is 
taking these tests, the patient’s parent or legal guardian will complete written questionnaires about 
the patient’s mood and emotions, behavior, daily living/functional skills and social skills with others.  
The parent/legal guardian can be in the same room during the testing but they cannot help their 
child with their tests.   
 
• 
Patients 18 years of age will complete computerized tests using an iPad and their own written 
questionnaires.  Parents/Legal guardians do not have testing to do with patients of this age. 
 
• 
Patients under 3 years of age will have an evaluation of overall functioning including language, 
motor and cognitive development done by a licensed psychologist.  Parents/legal guardians will 
also complete written questionnaires at the same time. 
 
Patient age at 
testing in years 
Testing being done 
Length of testing time  
for Patients 
Length of testing time for 
Parents/legal guardians 
1 
Patient: licensed psychologist 
Parent/legal guardian: written 
questionnaires 
~ 60 - 90 minutes 
~ 20 minutes 
2 
~ 50 minutes 
3 - 5 
Patient: computerized tests using  an 
iPad 
Parent/legal guardian: written 
questionnaires 
~ 10 minutes 
~ 50 minutes 
6 
~ 30 – 40 minutes 
~ 50 minutes 
7 - 9 
~ 30 – 40 minutes 
~ 50 - 55 minutes 
10 - 17 
~ 35 – 45 minutes 
~ 50 - 55 minutes 
18 
Patient: computerized tests using an 
iPad and written questionnaires 
~ 80 – 90 minutes 
NA 
 
 
NANT Biology Study (NANT 2004-05) 
If you choose to participate in this research, you will also be asked to join a companion NANT biology study 
to collect blood, bone marrow and tumor tissue (if available) and reports from radiology scans from patients 
with neuroblastoma. The biology study also provides a place (called NANT biorepository) where any leftover 
samples of tumor tissue or bone marrow and blood collected on this study could be transferred and stored. 
While you will be asked to join the Biology Study (NANT 2004-05), the decision to store/bank any leftover 

 
 
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samples is optional and will not affect your ability to participate in this treatment study with lorlatinib.  Your 
doctor will talk with you in detail about the NANT biology study and have you sign a separate consent form. 
 
Additional Tests in this Study 
We would like to do some extra tests called pharmacokinetic studies and biologic studies.  These tests will 
help us learn more about lorlatinib and may help children and adolescents 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 meaning you can decide whether you 
want to do them or not.  
 
Pharmacokinetic Studies: Determining Blood Levels of Lorlatinib – Required  
During this study blood samples will be collected to determine how much lorlatinib is in your blood (called 
pharmacokinetics). About 3mL (just over half a teaspoon) of blood will be drawn with each sample.  A total of 
9 blood samples will be obtained over 3 separate days during course 1 (Day 1, Day 2 and Day 15).  The total 
amount of blood drawn for testing will be about 27 mL (almost 5 ½ teaspoons). If you have a central line (such 
as a port or a Broviac) these samples can be drawn through that line or through a small tube placed in a vein 
in your hand or arm.  This amount of blood is considered safe to donate. Samples will be sent to a commercial 
laboratory contracted to perform these tests for the study. These samples will be the property of Pfizer and 
Pfizer may also use the PK Biological Samples for evaluation of the bioanalytical method. 
 
Other Biology Research Tests in this Study - Optional 
You will be asked if you want to participate in 3 optional research tests.  You can decide not to let the doctors 
do these tests and still be able to be treated as part of this study.  There are checkboxes at end of this form 
to mark whether you are willing to participate in these voluntary studies. The results of these research tests 
will not be shared with you or become part of your medical record.  These results would also not be used to 
make decisions about your care while enrolled on this study.    
 
• 
Using extra blood to look for genetic changes seen in tumor cells. 
Tumor cells often release small pieces of DNA into the blood stream where it can be detected by 
sensitive tests.  About 17mL (almost four teaspoons) of blood will be drawn at study entry and at 
each time disease evaluation testing is done (after cycles 2, 4, 6 and then every 4th cycle) to look at 
what genetic changes in your tumor may be seen over time from the small pieces of tumor DNA 
found in your blood. The blood will be sent to a commercial laboratory contracted to perform this 
testing for the study.  
 
• 
Comparing genetic changes between leftover tumor from a surgical procedure prior to tumor 
relapse (at diagnosis or when you had surgery done after diagnosis) to relapsed 
neuroblastoma tumor tissue and bone marrow aspirates and whether these changes affect 
how the tumor will respond to treatment with Lorlatinib. 
 Researchers would like to look at tumor tissue to determine if there are certain gene changes  
 present that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.   
 These tests would be done on tumor tissue remaining from diagnosis, or any previous surgery  
 where tumor tissue was removed (removal of primary tumor or removal of tumor at a relapse) in  
 the past. The tissue and bone marrow aspirates will be sent to a research laboratory at Children’s   
 Hospital of Philadelphia for testing.     
 
When You Have Finished Treatment with Lorlatinib  
After you stop treatment on this study, you will continue to have tests and scans done (listed below) to 
measure how much tumor is left. If test results show you have abnormal organ functions, tests are 
recommended by the study to be repeated monthly until test results are stable or normal. You doctor will 
tell you how often these tests and evaluations will be done. 
 
 

 
 
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Medical Tests after the Study: 
 
Physical exam  
Neuropsychological testing1 
Blood tests 
Bone marrow tests & various scans (CT/MRI, MIBG or PET) 
to check your tumor2 
Electrocardiogram (EKG) to 
check the heart rhythm3 
 
 
1The same neuropsychological testing and evaluation done before starting study treatment will be done at 
the end of treatment with lorlatinib.  The need for any further testing after this will be up to your doctor. 
 
2Bone marrow tests and various scans are done for checking the response of your tumor to treatment.  
These tests will be done at the end of a course and at certain times following treatment to monitor your 
tumor status. 
 
3Electrocardiogram (EKG) done at the end of the study to document if lorlatinib treatment has any effect on 
heart rhythm.  
 
A table detailing the tests and procedures required before, during and after the study has been attached to 
the end of this form (Consent Addendum 1). 
 
HOW LONG WILL I BE ON THIS STUDY?  
You can get up to 24 cycles with lorlatinib and chemotherapy or indefinitely if you are no longer receiving 
chemotherapy as long as you are not having bad side effects and as long as your tumor is not getting 
worse.   
 
After you stop treatment, you will continue to have tests and scans done to measure how much tumor is left. 
Your doctor will tell you how often these tests will be done. Researchers will continue to collect information 
about you for a lifetime. Information will be collected about whether you are still alive; whether your tumor has 
grown back and at what sites in the body; whether you have developed any side effects from the treatment; 
or whether you have developed any additional cancer. Your oncologist or family doctor will give the 
researchers this information at regular intervals. 
 
CAN I STOP BEING IN THE STUDY? 
Yes. If you are thinking about stopping your participation on this study, you should talk to your doctor before 
making a final decision so he/she can tell you how to do this safely.  
 
Your doctor may also stop you from taking part in this study at any time if he/she believes it is in your best 
interest; if you do not follow study rules; or if the study is stopped. 
 
WHAT ARE THE RISKS OF THE STUDY? 
This is a Phase 1 study.  A Phase 1 study looks at how common and serious side effects can be for each 
patient at a specific dose of a drug. In a Phase 1 study, some patients may have very serious side effects 
and could die as a result of these side effects. You may be one of those patients who have serious side 
effects as a result of participating in this Phase 1 study.  
 
In this study, researchers will be looking at side effects seen in patients taking different doses of lorlatinib 
as well as lorlatinib given together with chemotherapy.  
Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know 
all the side effects that may happen. Side effects may be mild or very serious. Other drugs may be given 
to make side effects less serious and more comfortable.   Many side effects go away soon after you stop 
taking the study medications but it is always possible that side effects can be serious, long lasting or may 
never go away. There is also a risk of death. Patients are watched carefully and treatment will be stopped 

 
 
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if bad side effects develop. There may also be risks we do not know about. You should talk to your doctor 
about any side effects that you have while taking part in this study.  
 
While on the study, you are at risk for the side effects listed below: 
 
Possible Risks of Lorlatinib: 
 
The following side effects are considered to be related to lorlatinib have been reported:  
Very Common  
(may affect 10 or more in 100 people) 
Common 
(may affect from 1 up to less than 10 in 100 people) 
• 
Increase in cholesterol and triglycerides 
(fats in your blood)  
• 
Effects on mood (for example, irritability 
and mood swings)  
• 
Effects on memory (for example, 
confusion, memory loss and disturbance 
of attention)  
• 
Effects on the peripheral nerves which are 
those outside of the brain and spinal cord, 
including tingling, numbness or pain in 
hands and feet)  
• 
Changes in vision (including double 
vision, perceived flashes or floaters of 
light, light intolerance, vision blurred, 
vision sharpness reduced and visual 
impairment) 
• 
Hypertension  
• 
Diarrhea  
• 
Constipation  
• 
Joint pain  
• 
Build-up of fluid in the body or extremities 
causing swelling (edema)  
• 
Fatigue (feeling tired and exhausted)  
• 
Increase in body weight 
• 
Increase in blood sugar levels 
• 
Hallucination and loss of contact with 
reality 
• 
Changes in mental status  
• 
Changes in speech (for example, slow 
speech or slurred speech) 
• 
Inflammation of the lungs (pneumonitis) 
which can cause shortness of breath and 
difficulty breathing. If severe, this can be 
life threatening.  
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
162 
 
 
The following events have also been reported in patients while they were taking lorlatinib, although the 
relationship to lorlatinib is uncertain:  
 
Very common (may affect 10 or more in 100 people) 
• 
Abnormalities in blood tests that may indicate liver damage 
• 
Abnormal pancreas tests 
• 
Decrease in hemoglobin in the blood that can cause weakness 
• 
Headache 
• 
Muscle pain 
• 
Difficulty sleeping 
• 
Rash 
 
Common (may affect from 1 up to less than 10 in 100 people) 
• 
Decrease of ejection fraction of the heart which may indicate severe heart problem 
• 
A sudden and temporary loss of consciousness (syncope) 
• 
Changes in the electrical activity of your heart that might lead to a heart rhythm problem and/or 
irregular heartbeat 
 
Uncommon (may affect less than 1 in 100 people) 
• 
Inflammation of the pancreas causing pain in the upper abdomen. This could become severe and 
may cause nausea and vomiting, fever and rapid heart rate. This could require hospitalization and 
may be life threatening 
• 
Suicidal thoughts  
• 
Psychosis 
 
Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised 
when driving or operating machines as patients may experience CNS effects.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
163 
 
 
Possible Side Effects of Cyclophosphamide: 
 
Likely 
Less Likely 
Rare But Serious 
• 
Loss of appetite 
• 
Nausea  
• 
Vomiting 
• 
Fewer white blood cells in the 
blood. 
○ 
A low number of white blood 
cells may make it easier to 
get infections. 
• 
Hair loss 
• 
Decreased ability of the body to 
fight infection  
• 
Absence  or decrease in the 
number of  sperm  which may be 
temporary or permanent which 
may decrease the ability to have 
children 
 
 
• 
Abdominal pain 
• 
Diarrhea 
• 
Fewer red blood cells and 
platelets in the blood 
○ 
A low number of red blood 
cells may make you feel 
tired and weak. 
○ 
A low number of platelets 
may cause you to bruise 
and bleed more easily. 
• 
Bleeding and inflammation of 
the urinary bladder 
• 
Absence  or decrease monthly 
periods which may be 
temporary or permanent and 
which may decrease the ability 
to have children 
 
• 
Temporary blurred vision 
• 
Nasal stuffiness with fast IV 
infusions 
• 
Irregular heart rate with fast IV 
infusions 
• 
Skin rash 
• 
Severe allergic reaction which 
can be life threatening with 
shortness of breath, low blood 
pressure, rapid heart rate 
chills and fever 
• 
Abnormal hormone function 
which may lower the level of 
salt in the blood  
• 
Heart muscle damage which 
may occur with very high 
doses and which may be fatal 
• 
Darkening of areas of the skin 
and finger nails 
• 
Fingernail changes 
• 
Slow healing of wounds 
• 
Infections  
• 
Infertility which is the inability to 
have children 
• 
Damage and scarring of lung 
tissue which may make you 
short of breath 
• 
A new cancer or leukemia 
resulting from this treatment. 
• 
Damage or scarring of urinary 
bladder tissue 
 

 
 
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Possible Side Effects of Topotecan: 
 
Likely 
Less Likely 
Rare But Serious 
• 
Diarrhea  
• 
Nausea 
• 
Vomiting 
• 
Constipation 
• 
Fewer white blood cells, red 
blood cells and platelets in the 
blood. 
o 
A low number of white 
blood cells can make it 
easier to get infections 
o 
A low number of red blood 
cells can make you feel 
tired and weak 
o 
A low number of platelets 
causes you to bruise and 
bleed more easily 
• 
Fever including fever with a low 
white blood cell count which 
could indicate infection and 
may require hospitalization and 
treatment with antibiotics 
• 
Pain which may be in your 
abdomen, back or bones 
• 
A feeling of weakness and/or 
tiredness 
• 
Temporary hair loss 
• 
Loss of appetite 
• 
Headache 
• 
Lack of muscle strength 
or weakness 
• 
Rash, hives, itching or a 
red bumpy rash 
• 
A mild lowering of the 
blood pressure which 
usually does not require 
treatment 
• 
Shortness of breath 
• 
Inflammation and/or 
sores in the mouth, 
throat and/or esophagus 
• 
Elevation in the blood of 
certain enzymes found in 
the liver which may 
indicate liver irritation or 
damage 
• 
An infection in the blood 
which will require 
admission to the hospital 
and treatment with 
antibiotics 
 
• 
Severe allergic reaction which can be 
life threatening with shortness of 
breath, low blood pressure and a 
rapid heart rate 
• 
Severe allergic reaction which can be 
life threatening with rapid build-up of 
fluid under the skin, in the lining of the 
intestine and possibly in the throat or 
swelling of the tongue which could 
make it difficult to breath. 
• 
Chest pain 
• 
Shaking chills  
• 
Elevation in the blood of certain 
enzymes or bilirubin found in the liver 
which could indicate liver irritation or 
damage 
• 
Numbness and tingling in the fingers 
and toes 
• 
Muscle or joint aches and pains 
• 
Bleeding into the tumor which may 
cause damage depending on the 
location of the tumor 
• 
Small amount of blood and/or protein 
in the urine or an elevation in blood 
creatinine which may indicate mild 
kidney damage 
 
 
 
 
 

 
 
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Growth Factors are not anti-cancer medicines.  It helps the growth of white blood cells that fight infection 
(filgrastim/pegfilgrastim).  
 
Possible Side Effects of Neupogen (Filgrastim): 
 
Likely  
(happens to 21-100 
children out every 
100 children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out every 100 children) 
• 
Aching or 
pain in 
bones. 
• 
Local irritation/pain at the site 
of the injection. 
• 
Higher than normal levels in 
the blood of uric acid and of 
liver enzymes which may 
indicate liver irritation or 
damage. 
• 
Fever 
• 
A low number of platelets in 
the blood which may cause 
you to bruise and bleed more 
easily. 
• 
Allergic reactions which can be life threatening 
with shortness of breath, low blood pressure, 
rapid heart rate, hives, facial swelling. This 
reaction is very rare and has been associated 
mainly with intravenous administration. 
• 
If you are known to have sickle cell disease , 
this drug may cause sickle cell crises  
• 
Severe damage to the spleen (an organ in the 
abdomen which stores blood cells) which could 
lead to pain and loss of blood into the abdomen 
or rupture of the spleen. 
• 
Difficulty breathing and lung damage that may 
be due to the white blood cells, stimulated by 
Pegfilgrastim , travelling to the lungs when they 
are inflamed or infected (Adult Respiratory 
Distress Syndrome)  
• 
Bone marrow dysfunction (MDS) or secondary 
leukemia in patients with very bad ongoing low 
white cell counts that require prolonged 
administration of this drug. 
• 
Worsening of skin rashes 
• 
Low Fever 
• 
Inflammation of blood vessels leading to a 
raised purple rash and bruising 
• 
Higher than normal white blood count. 
• 
Low blood pressure and/or increased heart rate 
• 
Wheezing or shortness of breath 
• 
Skin rash, hives or facial swelling 
 

 
 
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Possible Side Effects of Neulasta (Pegfilgrastim): 
 
Likely  
(happens to 21-100 
children out every 100 
children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out every 100 children) 
 
• 
Aching or 
pain in 
bones. 
 
• 
Local irritation at the site of 
the injection. 
• 
Headache 
• 
Higher than normal levels in 
the blood of uric acid and of 
liver enzymes which may 
indicate liver irritation or 
damage. 
• 
A low number of platelets in 
the blood which may cause 
you to bruise and bleed 
more easily. 
 
 
 
 
 
 
• 
Low grade fever 
• 
Allergic reactions which can be life threatening 
with shortness of breath, low blood pressure, 
rapid heart rate, hives, facial swelling. This 
reaction is very rare and has been associated 
mainly with intravenous administration. 
• 
Redness and flushing of the face and body. 
• 
Enlarged spleen 
• 
Severe damage to the spleen (an organ in the 
abdomen which stores blood cells) which could 
lead to pain and loss of blood into the abdomen. 
• 
If you are known to have sickle cell disease , this 
drug may cause sickle cell crises  
• 
Markedly higher than normal white blood cell 
count which may be associated with fever and 
red, often painful patches on the skin (Sweet's 
syndrome). 
• 
Difficulty breathing and lung damage that may be 
due to the white blood cells, stimulated by 
Pegfilgrastim, travelling to the lungs when they 
are inflamed or infected (Adult Respiratory 
Distress Syndrome) 
  
Possible Risks to Unborn Child 
Patients who agree to participate in this study should not become pregnant while on this study. Lorlatinib 
may cause fetal harm when administered to a pregnant woman and is not recommended during 
pregnancy or for women of childbearing potential not using contraception. Women of childbearing 
potential should use nonhormonal methods of birth control. If a hormonal method of birth control is 
unavoidable, then a condom must be used in combination with the hormonal method. Female patients 
must continue to follow these birth control guidelines for 21 days after finishing the study. Male patients 
must wear condoms as one of their forms of birth control for the duration of the study and for 97 days 
after finishing the study. Further contraception use should be discussed with your personal physician. If 
you or your partner becomes pregnant while you are participating in this study, please notify your doctor 
immediately.  For more information about risks and side effects, ask your doctor. 
 
Possible Long Term Side Effects of This Treatment 
Side effects in adults treated with lorlatinib have occurred while patients have been receiving the drug or 
shortly after finishing the drug.  It is not known if some side effects may be seen only after a long time after 
finishing treatment with lorlatinib.   
 
Possible Risks from Having Blood Drawn 
The risks from having your blood taken are minimal, but can include an infection or a blood clot. Experienced 
doctors or nurses will perform these blood draws to minimize this risk.   
 
Unknown Risks 
The treatment may have side effects that no one knows about yet.  The researchers will let you know if they 
learn anything that might make you change your mind about participating in the study. 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
There may or may not be direct medical benefit to you. The information learned from this study may or may 
not benefit other children or young people with solid cancers in the future. 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
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WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
There are other options for you instead of this treatment. Instead of being in this study, you have these 
options: 
 
• 
Treatment with other chemotherapy medicines  
• 
Treatment with other experimental agents that may be available. 
• 
No neuroblastoma therapy at this time, with care to help you feel more comfortable. 
 
Please talk about these options with your doctor. 
 
 
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. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance and data 
analysis include: 
• 
New Approaches to Neuroblastoma Therapy (NANT) Consortium at Children’s Hospital Los 
Angeles in Los Angeles, CA.  The NANT Consortium identifies you by a number. 
• 
Independent auditor evaluating quality assurance for the NANT Consortium. 
• 
The National Cancer Institute (NCI) and other governmental agencies, like the Food and Drug 
Administration (FDA) or Health Canada, involved in keeping research safe for people. 
• 
Foundation Medicine, Inc. who is a collaborator on this study.  
• 
Pfizer Inc., the pharmaceutical company which makes lorlatinib. 
 
NANT has received a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects. Information about the certificate is included at the end 
of this consent. 
 
Because this study involves the treatment of a medical condition, a copy of this consent form will be placed 
in your medical record. This will allow the doctors that are caring for you to obtain information about what 
medications or procedures you are receiving in the study and treat you appropriately. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
Taking part in this study may lead to added costs to your insurance company.  Your health insurance 
company will be billed for many expenses associated with the costs of this study.  These expenses include 
medications, treatments, hospital charges, and doctors’ fees related to your participation in this study.   
 
Lorlatinib and the flavoring agent (Ora-Plus®) are being provided free of charge for use in this study, but 
the costs associated with administering the drug is normally covered by your insurance company. 
Cyclophosphamide and topotecan is normally covered by your insurance company. The cost of doing a 
heart test called an EKG and neuropsychological testing at several time points during your participation in 
the study with Lorlatinib is being done as part of research and will be paid for by the study.  
The special research blood and tissue studies will be done at no cost to you.  However, you or your health 
plan may need to pay for the costs of the supplies and personnel who draw the blood from you for these 
tests. 
  
You may have to pay for other things during this study, such as but not limited to, your time, the cost of 
food you buy while you are being treated at the hospital, car fare, travel to and from the hospital for 
treatment, parking, and baby sitter fees. 
 

 
 
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Taking part in this study may lead to added costs that may not be covered by your insurance company. 
Please ask about any expected added costs or insurance problems. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .   You can print a copy of 
the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that 
you have been injured because of taking part in this study. You can tell the doctor in person or call him/her 
at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study. You and/or your 
health plan will be charged for this treatment.  The study will not pay for medical treatment.  
 
WHAT ARE MY RIGHTS AS A STUDY PARTICIPANT? 
Taking part in this study is your choice. You may choose not to take part or not take part in the study. If you 
decide to take part in this study, you may remove yourself from 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. If you 
remove yourself from the study, we will still take care of you. We will explain what stopping the treatment 
may do and we will offer other treatments if they are available.  
 
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 case of injury resulting from this study, you do not lose any of you legal rights to seek payment by signing 
this form. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing data from this 
research throughout the study.  We will tell you about new information from this Board or other studies that 
may affect your health or willingness to stay in the study. 
 
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).  
 
 
WHO IS FUNDING THIS RESEARCH STUDY? 
This study is supported by Pfizer, Inc. Pfizer is a drug company that makes the drug being studied in this 
research project. Pfizer is giving money to Children's Hospital for some of the costs of the study. The results 
of the study will be reported to Pfizer. If the study shows that lorlatinib may be useful for a new purpose, 
this could benefit Pfizer financially. 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
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The Children’s Hospital Los Angeles/NANT is also providing funding for this study. 
 
Dr. Mossé at Children’s Hospital of Philadelphia, one of the principal investigators of this study, has served 
as a paid consultant to Pfizer. Her participation in this research has been reviewed and approved, subject 
to management, according to CHOP’s/NANT Conflict of Interest Policy.  
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the NCI’s Cancer Information Service at 
 
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615 
 
You may visit the NCI Web sites 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/ 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  
This website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this website at any time. 
 
You will get a copy of this consent form. If you want more information about this study, ask your doctor. 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
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CONSENT FOR EXTRA STUDIES FOR RESEARCH  
 
The following tests are optional for all patients in the study. You may still participate in the study 
even if you do not agree to these tests. 
 
1. Using extra blood to look for genetic changes seen in tumor cells 
Initial next to YES if you agree to let researchers take almost 4 extra teaspoons (17mL) at study entry 
and each time a disease evaluation is done)  to look at what genetic changes in your tumor can be seen 
in your blood over time before and after treatment with lorlatinib.  This blood would be drawn at a time 
when blood was being drawn for clinical purposes.  The blood will be sent to Foundation Medicine Inc. 
for analysis who is a collaborator on this study. The results of these tests will be confidential and not 
made available to you or your treating physician. 
 
Initial next to NO, if you do not want researchers to take extra blood above what is needed for clinical 
purposes. 
 
_______Yes       
_______No    
 
 
2. Comparing genetic changes between tumor leftover from a surgical procedure prior to relapse 
(diagnosis or second look) to relapsed neuroblastoma tumor tissue and bone marrow aspirates 
and whether these changes affect how the tumor will respond to treatment with Lorlatinib. 
 
Initial next to YES, if you agree (and if there is tumor remaining)  to let this tumor be sent to a laboratory 
so researchers can compare these samples and determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  The results of 
these tests will be confidential and not made available to you or your treating doctor. 
 
Initial next to NO if you do not want leftover tumor from an earlier procedure to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely to 
respond to the drug lorlatinib. 
 
_______Yes      _______No   
 
 
Initial next to YES, if you agree to let extra bone marrow aspirates be collected to be sent to a laboratory 
so researchers can compare these samples and determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  The results of 
these tests will be confidential and not made available to you or your treating doctor. 
 
Initial next to NO if you do not want these bone marrow aspirates collected to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely to 
respond to the drug lorlatinib. 
 
_______Yes      _______No   
 
 
 
 
 
 
 

 
 
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STATEMENT OF CONSENT 
 
I have already read the information in this informed consent document. I have read all the attachments that 
were included with this informed consent document. I have asked all of my questions and I have gotten 
answers. I agree to enroll myself (my child) in this study. 
 
 
_____________________________________ 
Patient Name 
 
 
______________________________________  
 
_____/_____/_____ 
Print Name of Parent or Guardian 
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Parent or Guardian  
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Patient (If > 7 years old) 
 
 
 
 
Date 
 
 
___________________________________________ 
 
_____/_____/______ 
Signature of Physician or  
 
 
 
 
 
Date 
Responsible Investigator 
 
_______________________________________ 
 
____/_____/______ 
Signature of Witness 
 
 
 
 
 
 
Date 
 
 
_______________________________________ 
 
____/_____/______ 
Signature of Translator  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
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Consent Addendum I: Tests That Will Be Done On This Study 
Observation 
Before Entry 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of Therapy 
Physical exam 
including neurological 
exam 
X 
Weekly 
Start of cycle 
Start of each cycle 
X 
Routine blood tests** 
(Blood counts, 
electrolytes, liver, 
kidney function, 
function of pancreas-
amylase/lipase) 
X 
Weekly for other 
tests and twice 
weekly for blood 
counts 
Weekly for blood counts and twice 
during cycle for all other blood 
tests   
Start of each cycle 
and weekly for blood 
counts 
X 
Routine Blood tests** 
(Fasting cholesterol, 
triglycerides, glucose) 
X 
Every other 
week  
Start of cycle  
Start of each cycle  
X 
Hemoglobin 
A1c 
(HbA1c)  
X  
 
Start of cycle  
With Disease 
Evaluations in 
Courses 4 and 6 and 
after every 4 courses 
thereafter  
X 
Blood tests for 
cholesterol, 
triglycerides and 
function of the 
pancreas 
(amylase/lipase) 
X 
Weekly 
Start of cycle 
Start of each cycle 
X 
Pregnancy test 
(All females10 years 
of age and older) 
X 
 
Start of cycle 
Start of each cycle 
 
Heart rhythm test 
(EKG)  
X 
One hour after 
day 1 treatment 
is finished 
End of cycle 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
Neuropsychological 
Testing  
Within one week 
before starting 
treatment 
End of cycle 
End of cycle 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
 Neuropsychological 
evaluation with 
licensed psychologist 
for patients less than 
3 years of age 
Within one week 
before and up to 
two weeks after 
starting 
treatment  
 
End of cycle 
End of cycle 6, 10 
and then every 8 
cycles thereafter 
X 
Submit Patient 
Treatment Diaries 
 
X 
X 
X 
X 
Blood for Lorlatinib 
drug level tests (PK - 
Required) 
 
Day 1: 3 times 
Day 2: 1 time 
Day 15: 5 times 
 
 
 
Blood for circulating 
tumor cells (Optional) 
X 
 
With disease evaluation 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
 

 
 
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Bone Marrow 
Aspirate (Optional) 
X 
 
With disease evaluation 
End of cycle (4,6, 
and every 4th cycle 
thereafter) 
 
Sampling of leftover 
tumor tissue 
(Optional) 
Leftover tumor tissue can be sent at any time during the study 
 
Tests done at Disease Evaluation 
Bone marrow 
aspirate and biopsy 
X 
 
Week 4 
 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
CT/MRI scans and/or 
MIBG/PET scans 
Blood and bone 
marrow for NANT 
Biology study# 
# Patients enrolled in the companion biology study may have additional samples of blood and bone marrow collected at study entry 
and with each disease evaluation time point. Please look at the biology study (NANT 2004-05) consent form for more information. 
**Blood draws can be done more often if needed at the discretion of your study doctor 

 
 
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Consent Addendum II 
Certificate of Confidentiality Information 
 
NANT 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. 
 

 
 
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APPENDIX VIII: DOSE EXPANSION COHORT A2: PATIENTS > 18 YEARS OF AGE SAMPLE 
CONSENT 
 
NANT 2015-02:  PHASE 1 STUDY OF LORLATINIB, AN ORAL SMALL MOLECULE INHIBITOR OF 
ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY NEUROBLASTOMA 
 
COHORT A2: PATIENTS 18 YEARS OF AGE AND OLDER  
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol. 
 
WHAT IS THIS STUDY ABOUT? 
This study is a clinical trial, a type of research study. Clinical trials include only patients who choose to take 
part. Please take your time to make your decision about participating. You may discuss your decision with 
your friends, family, and health care team. If you have any questions, you may ask your doctor. 
 
You are being asked to participate in this study because you have a kind of cancer called neuroblastoma. 
It may be that your cancer went away for a while but has grown back (relapsed) or it may be that it has 
never gone away (persistent or resistant tumor) after standard treatment. Standard treatment may have 
included chemotherapy, surgery, radiation therapy, high-dose chemotherapy with a stem cell transplant 
and/or immunotherapy. 
 
WHY IS THIS STUDY BEING DONE? 
 
The Purposes Of This Study Are: 
 
• 
To find the highest dose of lorlatinib that can be given to adults with refractory or relapsed 
neuroblastoma without causing severe side effects.  
 
• 
To learn about the side effects of the drug lorlatinib when given to adults. 
 
• 
To determine if your tumor gets smaller after treatment with lorlatinib. 
 
• 
To measure the levels of lorlatinib in the blood  
 
• 
To look at genetic changes in tumor DNA found in the blood during treatment. 
 
• 
To look at genetic changes in tumor tissue to see if they affect response to lorlatinib. 
 
• 
To describe the amount of neuroblastoma tumor found in the blood and bone marrow by testing 
samples with a new test (called NB5 assay). 
 
The Research Is Being Done Because: 
Currently there is no known effective treatment for your type of cancer.  We are testing new experimental 
drugs such as lorlatinib in the hopes of finding a drug that may be effective against neuroblastoma tumors 
that have come back (relapsed) or that have never gone away (persistent/refractory) after treatment with 
standard therapy.  
 
This study involves the use of an experimental drug called lorlatinib.  In laboratory testing, lorlatinib blocks the 
Anaplastic Lymphoma Kinase (ALK) gene. ALK may be important in the growth of certain types of cancer 
cells such as neuroblastoma.  Lorlatinib is considered experimental because it has not been proven to work 
in a situation like yours.  Lorlatinib has been approved by the United States Food and Drug Administration 
(FDA) to treat adults with non-small cell lung cancer, a different cancer than yours.It is not approved for 
neuroblastoma.  Lorlatinib has been used only in a small number of adults so there is a lot we do not know 
about it yet.  In these previous studies, the recommended dose of lorlatinib that can be given safely was 

 
 
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determined for adults. In this study, we are also studying higher dose levels. Adults will receive 2 dose 
levels of lorlatinib on this cohort. All patients enrolled on this study are known to have a defect in the ALK 
gene in their tumor before they start treatment.   
 
In this study, the lorlatinib dose you will be given is higher than the recommended dose given to adults with 
other cancers who have been treated with lorlatinib.  This is because based on laboratory studies, it is 
thought that higher levels of lorlatinib might be needed to have an effect on neuroblastoma.  Other adults 
have been treated at similar higher dose levels in the past and side effects experienced were temporary 
and resolved after stopping or decreasing the dose of lorlatinib.  You will be closely monitored for any side 
effects with this treatment.    
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
There will be about 60-75 patients enrolling on the 4 study cohorts. You have been given this consent 
because the planned enrollment is on cohort A2. When you join the study, you will be assigned a certain 
lorlatinib dose. Cohort A2 will test up to 2 lorlatinib doses. There will be a a minimum of 20 patients enrolling 
on these two doses. Investigators are trying to decide the highest dose of lorlatinib that can be given without 
bad side effects.  
 
WHAT WILL HAPPEN TO ME IF I TAKE PART IN THIS STUDY? 
 
Before You Begin the Study  
Your doctor will have previously sent your tumor for genetic testing and these results showed your tumor 
has a defect in the ALK gene which allows you to be considered for participation in this study. 
 
You will need to have the following exams, tests or procedures to find out if you can take part in the study. 
Most of these exams, tests or procedures are part of regular cancer care and may be done even if you do 
not join the study. These tests will also be done at various times throughout the study and at the end of the 
study.  The purpose of these tests is to see how well the treatment works and to measure the status of your 
neuroblastoma. If you have had some of them recently, they may not need to be repeated. This will be up 
to your doctor. 
 
A medical history & physical exam 
Bone marrow tests3 to check your tumor 
Blood tests1 
Various scans4 to check your tumor 
Pregnancy test (urine or blood)2 
Electrocardiogram (EKG) to check the heart rhythm5 
 
Neuropsychological testing6 
 
1Some blood tests (cholesterol and fat digestion [triglycerides]) may need to be done on an empty stomach, 
so you cannot eat or drink anything other than water for 8-10 hours before these tests are done (called 
fasting).   Your doctor or nurse will tell you if it is necessary for you to fast before these blood tests are 
done. 
 
2If you are a female at least 10 years old or who could have children, you will have a pregnancy test done 
by the doctor the week before starting treatment and then before each cycle of treatment begins. Both you 
and your parent/legal guardian (if applicable) will be informed of a positive pregnancy test.  All men and 
women who could have children must either agree to practice abstinence from heterosexual intercourse or 
use two effective methods of birth control for as long as they participate in this study.  
 
3Bone marrow tests are done by inserting a needle into the hip bone to remove the marrow which is inside 
the bone. 
 
4Various scans are done for diagnosis and checking the response of the tumor to treatment. These may 
include CT and /or MRI scans and MIBG or PET scans. We will recommend scans specific for your case 
and we will answer your questions about these scans. 

 
 
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5Electrocardiogram (EKG) to document your heart rhythm before beginning lorlatinib treatment.  
 
6Central nervous system effects (speech, memory and mood changes) were seen in previous studies 
treating adults with Lorlatinib.  Neuropsychological testing will be done at within one week of starting 
treatment and at different times during this study to monitor for any changes in thinking skills, behavior and 
mood.   Please see the section on Neuropsychological testing below in “During this Study” for more details 
on what tests are done and when they are done during this study.  
 
During the Study   
If the exams, tests and procedures show that you can be in the study, and you choose to take part, lorlatinib 
will be given for 28 days.  This entire period is called a cycle with each treatment cycle being 28 days long.  
You may continue to take lorlatinib for an unlimited number of cycles unless you develop serious side effects 
or your tumor worsens. 
 
Lorlatinib will be given by mouth once a day followed by a small glass of water.  If you vomit lorlatinib within 
20 minutes of taking the dose for the day, that dose can be repeated.  This is the only time a dose of 
lorlatinib can be repeated.  
 
Lorlatinib will be available as a tablet.  If you are unable to swallow the tablets whole, you will be instructed 
on how to make a liquid lorlatinib solution at home by mixing the lorlatinib tablets with water and a flavoring 
agent (Ora-Plus®).  Your nurse or doctor will help you decide what is best for you and will make sure you 
have the proper directions for taking this medication. 
 
You will be given a patient diary at the beginning of each cycle of lorlatinib.  Use the diary to record the date 
and time you take the drug, all vomited and missed doses, side affects you experience and any other 
medications and supplements you are taking.  The diary should be returned to clinic along with the 
medication bottle (even if it is empty) weekly during cycle 1 and then after each treatment cycle of lorlatinib.  
This will help us to know how much of the drug you take and how it made you feel. 
 
During the study you will have tests and procedures done to check for side effects from taking lorlatinib and 
to see how your tumor is doing.  Many of these tests are part of regular cancer care but you may have them 
done more often because you are on the study: 
 
Physical exam 
Electrocardiogram (EKG) to test heart rhythm3 
Blood tests1 
Bone marrow tests & various scans (CT/MRI, MIBG or 
PET) to check your tumor4 
Pregnancy test (urine or blood)2 
Neuropsychological testing5 
 
1Some blood tests (cholesterol and fat digestion) can only be done on an empty stomach, so patients cannot 
eat or drink anything other than water for 8-10 hours before these tests are done.   
 
2A urine or blood pregnancy test will be done before each treatment cycle begins if you are a female who 
could have children. Both you and your parent/legal guardian will be informed of a positive pregnancy test. 
One Treatment Cycle  
 (Cohort A2: adults and children/adolescents higher BSA group meeting adult dosing 
criteria) 
Week 1 
Week 2 
Week 3 
Week 4 
Days 1 - 7 
Days 8 – 14 
Days 15 - 21 
Days 22 - 28 
 
Lorlatinib once a day 
 

 
 
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All men and women who could have children must continue to practice abstinence from heterosexual 
intercourse or use two effective methods of birth control for as long as they participate in this study.  
 
3Electrocardiogram (EKG) done before starting study treatment will be repeated at certain times during the 
study to document if lorlatinib treatment has any effect on heart rhythm. 
 
4Bone marrow tests and various scans are done for checking the response of your tumor to treatment.  
These tests will be done at certain times during the study to look at response to lorlatinib and check that 
your tumor has not gotten worse. 
 
5Neuropsychological Testing 
Neuropsychological evaluations try to understand how changes in the health of the brain may affect 
behavior or mood and how well a person is able to pay attention, remember things or solve problems.  Since 
effects on speech, memory and mood were seen in a small number of adults receiving lorlatinib, 
neuropsychological testing will be done to monitor for changes in thinking skills, behavior and mood at 
different times during this study.  A table at the end of the consent lists how often neuropsychological testing 
will be done during the study.  Testing methods are based on the age of the patient and include 
computerized tests using an iPad, written questionnaires and evaluations by a licensed psychologist.  
Parents or legal guardians of patients less than 18 years of age will also participate by completing written 
questionnaires at the same time their child is being tested.   
 
The results of the neuropsychological testing will be told to your doctor and entered as part of your medical 
record. Neuropsychological results will be used to make decisions about your care while enrolled on this 
study.  If the testing results show areas of concern, you may be given more frequent testing as well as 
referrals for other care if needed.  During testing, patients may skip questions that are stressful and may 
stop taking the tests at any time.  Testing can be done as part of the clinic visit.  You will need to talk with 
your doctor and nurse about scheduling to do these tests at times that are workable for you and your child. 
 
• 
Patients 18 years of age and older will complete computerized tests using an iPad and their own 
written questionnaires.  Parents/Legal guardians do not have testing to do with patients of this age. 
 
 
Patient age at 
testing in years 
Testing being done 
Length of testing time  
for Patients 
Length of testing time for 
Parents/legal guardians 
1 
Patient: licensed psychologist 
Parent/legal guardian: written 
questionnaires 
~ 60 - 90 minutes 
~ 20 minutes 
2 
~ 50 minutes 
3 - 5 
Patient: computerized tests using an 
iPad 
Parent/legal guardian: written 
questionnaires 
~ 10 minutes 
~ 50 minutes 
6 
~ 30 – 40 minutes 
~ 50 minutes 
7 - 9 
~ 30 – 40 minutes 
~ 50 - 55 minutes 
10 - 17 
~ 35 – 45 minutes 
~ 50 - 55 minutes 
18 – 25 
Patient: computerized tests using an 
iPad and written questionnaires 
~ 80 - 90 minutes 
NA 
26+ 
 
 
 
 
 
 
 
 

 
 
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NANT Biology Study (NANT 2004-05) 
You will also be expected to join a companion NANT biology study to collect blood, bone marrow and tumor 
tissue (if available) and reports from radiology scans from patients with neuroblastoma. The biology study 
also provides a place (called NANT biorepository) where any leftover samples of tumor tissue or bone 
marrow and blood collected on this study could be transferred and stored. While you will be asked to join 
the Biology Study (NANT 2004-05), the decision to store/bank any leftover samples is optional and will not 
affect your ability to participate in this treatment study with Lorlatinib.  Your doctor will talk with you in detail 
about the NANT biology study and have you sign a separate consent form. 
 
Additional Tests in this Study 
We would like to do some extra tests called pharmacokinetic studies and biologic studies.  These tests will 
help us learn more about lorlatinib and may help children and adolescents 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 meaning you can decide whether you 
want to do them or not.  
 
Pharmacokinetic Studies:  Determining Blood Levels of Lorlatinib – Required 
During this study blood samples will be collected to determine how much lorlatinib is in your blood (called 
pharmacokinetics). About 3mL (just over half a teaspoon) of blood will be drawn with each sample.  A total of 
9 blood samples will be obtained over 3 separate days during course 1 (Day 1, Day 2 and Day 15).  The total 
amount of blood drawn for testing will be about 27 mL (almost 5 ½ teaspoons). If you have a central line (such 
as a port or a Broviac) these samples can be drawn through that line or through a small tube placed in a vein 
in your hand or arm.  This amount of blood is considered safe to donate. Samples will be sent to a commercial 
laboratory contracted to perform these tests for the study. These samples will be the property of Pfizer and 
Pfizer may also use the PK Biological Samples for evaluation of the bioanalytical method. 
 
Other Biology Research Tests in this Study – Optional 
You will be asked if you want to participate in 3 optional research tests.  You can decide not to let the doctors 
do these tests and still be able to be treated as part of this study.  There are checkboxes at end of this form 
to mark whether you are willing to participate in these voluntary studies. The results of these research tests 
will not be shared with you or become part of your medical record.  These results would also not be used to 
make decisions about your care while enrolled on this study.    
 

 
 
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• 
Using extra blood to look for genetic changes seen in tumor cells. 
Tumor cells often release small pieces of DNA into the blood stream where it can be detected by 
sensitive tests.  About 17mL (almost four teaspoons) of blood will be drawn at study entry and at 
each time disease evaluation testing is done (after cycles 2, 4, 6 and then every 4th cycle) to look at 
what genetic changes in your tumor may be seen over time from the small pieces of tumor DNA 
found in your blood. The blood will be sent to a commercial laboratory contracted to perform this 
testing for the study. 
 
• 
Comparing genetic changes between leftover tumor from an earlier procedure (diagnosis or 
second look) to relapsed neuroblastoma tumor tissue and bone marrow aspirates and 
whether these changes affect how the tumor will respond to treatment with Lorlatinib. 
Researchers would like to look at tumor tissue to determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  These tests 
would be done on tumor tissue remaining from diagnosis, or any previous surgery where tumor 
tissue was removed (removal of primary tumor or removal of tumor at a relapse) in the past. The 
tissue and bone marrow aspirates will be sent to a research laboratory at Children’s Hospital of 
Philadelphia for testing.   
 
When you have finished treatment with Lorlatinib  
After you stop treatment on this study, you will continue to have tests and scans done (listed below) to 
measure how much tumor is left. If test results show you have abnormal organ functions, tests are 
recommended by the study to be repeated monthly until test results are stable or normal. You doctor will 
tell you how often these tests and evaluations will be done. 
 
Medical Tests after the Study: 
 
Physical exam  
Neuropsychological testing1 
Blood tests 
Bone marrow tests and Various scans (CT/MRI, MIBG or 
PET) to check your tumor2 
Electrocardiogram (EKG) to 
check the heart rhythm3 
 
 
1The same neuropsychological testing and evaluation done before starting study treatment will be done at 
the end of treatment with lorlatinib.  The need for any further testing after this will be up to your doctor. 
 
2Bone marrow tests and various scans are done for checking the response of your tumor to treatment.  
These tests will be done at the end of a course and at certain times following treatment to monitor your 
tumor status. 
 
3 Electrocardiogram (EKG) done at the end of the study to document if lorlatinib treatment has any effect 
on heart rhythm.  
 
A table detailing the tests and procedures required before, during and after the study has been attached to 
the end of this form (Consent Addendum 1). 
 
HOW LONG WILL I BE ON THIS STUDY?  
You can get an unlimited number of treatment cycles with lorlatinib as long as you are not having bad side 
effects and as long as your tumor is not getting worse.   
 
After you stop treatment, you will continue to have tests and scans done to measure how much tumor is left. 
Your doctor will tell you how often these tests will be done. Researchers will continue to collect information 
about you for a lifetime. Information will be collected about whether you are still alive; whether your tumor has 
grown back and at what sites in the body; whether you have developed any side effects from the treatment; 

 
 
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or whether you have developed any additional cancer. Your oncologist or family doctor will give the 
researchers this information at regular intervals. 
 
CAN I STOP BEING IN THE STUDY? 
Yes. If you are thinking about stopping your participation on this study, you should talk to your doctor before 
making a final decision so he/she can tell you how to do this safely.  
 
Your doctor may also stop you from taking part in this study at any time if he/she believes it is in your best 
interest; if you do not follow study rules; or if the study is stopped. 
 
WHAT ARE THE RISKS OF THE STUDY? 
This is a Phase 1 study.  A Phase 1 study looks at how common and serious side effects can be for each 
patient at a specific dose of a drug. In a Phase 1 study, some patients may have very serious side effects 
and could die as a result of these side effects. You may be one of those patients who have serious side 
effects as a result of participating in this Phase 1 study.  
 
In this study, researchers will be looking at side effects seen in patients taking different doses of lorlatinib. 
Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know 
all the side effects that may happen. Side effects may be mild or very serious. Other drugs may be given 
to make side effects less serious and more comfortable (such as for nausea, headache or reaction to 
lorlatinib). Many side effects go away soon after you stop taking the study medications but it is always 
possible that side effects can be serious, long lasting or may never go away. There is also a risk of death. 
Patients are watched carefully and treatment will be stopped if bad side effects develop. There may also 
be risks we do not know about. You should talk to your doctor about any side effects that you have while 
taking part in this study.  
 
While on the study, you are at risk for the side effects listed 
 below: 
 
Possible Risks of Lorlatinib 
 
The following side effects are considered to be related to lorlatinib have been reported:  
Very Common  
(may affect 10 or more in 100 people) 
Common 
(may affect from 1 up to less than 10 in 100 people) 
• 
Increase in cholesterol and triglycerides 
(fats in your blood)  
• 
Effects on mood (for example, irritability 
and mood swings)  
• 
Effects on memory (for example, 
confusion, memory loss and disturbance 
of attention)  
• 
Effects on the peripheral nerves which are 
those outside of the brain and spinal cord, 
including tingling, numbness or pain in 
hands and feet)  
• 
Changes in vision (including double 
vision, perceived flashes or floaters of 
light, light intolerance, vision blurred, 
• 
Hallucination and loss of contact with 
reality 
• 
Changes in mental status  
• 
Changes in speech (for example, slow 
speech or slurred speech) 
• 
Inflammation of the lungs (pneumonitis) 
which can cause shortness of breath and 
difficulty breathing. If severe, this can be 
life threatening.  
 
 
 
 

 
 
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vision sharpness reduced and visual 
impairment) 
• 
Hypertension  
• 
Diarrhea  
• 
Constipation  
• 
Joint pain  
• 
Build-up of fluid in the body or extremities 
causing swelling (edema)  
• 
Fatigue (feeling tired and exhausted)  
• 
Increase in body weight 
• 
Increase in blood sugar levels 
 
 
The following events have also been reported in patients while they were taking lorlatinib, although the 
relationship to lorlatinib is uncertain:  
 
Very common (may affect 10 or more in 100 people) 
• 
Abnormalities in blood tests that may indicate liver damage 
• 
Abnormal pancreas tests 
• 
Decrease in hemoglobin in the blood that can cause weakness 
• 
Headache 
• 
Muscle pain 
• 
Difficulty sleeping 
• 
Rash 
 
Common (may affect from 1 up to less than 10 in 100 people) 
• 
Decrease of ejection fraction of the heart which may indicate severe heart problem 
• 
A sudden and temporary loss of consciousness (syncope) 
• 
Changes in the electrical activity of your heart that might lead to a heart rhythm problem and/or 
irregular heartbeat 
 
Uncommon (may affect less than 1 in 100 people) 
• 
Inflammation of the pancreas causing pain in the upper abdomen. This could become severe and 
may cause nausea and vomiting, fever and rapid heart rate. This could require hospitalization and 
may be life threatening 
• 
Suicidal thoughts 
• 
Psychosis 
 
Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised 
when driving or operating machines as patients may experience CNS effects.  
 
 
 
 
z 

 
 
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  Possible Risks to Unborn Child 
Patients who agree to participate in this study should not become pregnant while on this study. Lorlatinib 
may cause fetal harm when administered to a pregnant woman and is not recommended during 
pregnancy or for women of childbearing potential not using contraception. Women of childbearing 
potential should use nonhormonal methods of birth control. If a hormonal method of birth control is 
unavoidable, then a condom must be used in combination with the hormonal method. Female patients 
must continue to follow these birth control guidelines for 21 days after finishing the study. Male patients 
must wear condoms as one of their forms of birth control for the duration of the study and for 97 days 
after finishing the study. Further contraception use should be discussed with your personal physician. If 
you or your partner becomes pregnant while you are participating in this study, please notify your doctor 
immediately.  For more information about risks and side effects, ask your doctor. 
 
Possible Long Term Side Effects of Treatment with Lorlatinib 
Side effects in adults treated with lorlatinib have occurred while patients have been receiving the drug or 
shortly after finishing the drug.  It is not known if some side effects may be seen only after a long time after 
finishing treatment with lorlatinib.   
 
Possible Risks from Having Blood Drawn 
The risks from having your blood taken are minimal, but can include an infection or a blood clot. Experienced 
doctors or nurses will perform these blood draws to minimize this risk.   
 
Unknown Risks 
The treatment may have side effects that no one knows about yet.  The researchers will let you know if they 
learn anything that might make you change your mind about participating in the study. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
There may or may not be direct medical benefit to you. The information learned from this study may or may 
not benefit other children, young people and adults with solid cancers in the future. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
There are other options for you instead of this treatment. Instead of being in this study, you have these 
options: 
 
• 
Treatment with other chemotherapy medicines  
• 
Treatment with other experimental agents that may be available. 
• 
No neuroblastoma therapy at this time, with care to help you feel more comfortable. 
Please talk about these options with your doctor. 
 
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. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance and data 
analysis include: 
• 
New Approaches to Neuroblastoma Therapy (NANT) Consortium at Children’s Hospital Los 
Angeles in Los Angeles, CA.  The NANT Consortium identifies you by a number. 
• 
Independent auditor evaluating quality assurance for the NANT Consortium. 
• 
The National Cancer Institute (NCI) and other governmental agencies, like the Food and Drug 
Administration (FDA) or Health Canada, involved in keeping research safe for people. 
• 
Foundation Medicine, Inc. who is a collaborator on this study.  
• 
Pfizer Inc., the pharmaceutical company which makes lorlatinib. 

 
 
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NANT has received a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects. Information about the certificate is included at the end 
of this consent. 
 
Because this study involves the treatment of a medical condition, a copy of this consent form will be placed 
in your medical record. This will allow the doctors that are caring for you to obtain information about what 
medications or procedures you are receiving in the study and treat you appropriately. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
Taking part in this study may lead to added costs to your insurance company.  Your health insurance 
company will be billed for many expenses associated with the costs of this study.  These expenses include 
medications, treatments, hospital charges, and doctors’ fees related to your participation in this study.   
 
Lorlatinib and the flavoring agent (Ora-Plus®) are being provided free of charge for use in this study, but 
the costs associated with administering the drug is normally covered by your insurance company.  The cost 
of doing a heart test called an EKG and neuropsychological testing at several time points during your 
participation in the study with lorlatinib is being done solely as part of research and will be paid for by the 
study.   
 
The special research blood and tissue studies will be done at no cost to you.  However, you or your health 
plan may need to pay for the costs of the supplies and personnel who draw the blood from you for these 
tests. 
  
You may have to pay for other things during this study, such as but not limited to, your time, the cost of 
food you buy while you are being treated at the hospital, car fare, travel to and from the hospital for 
treatment, parking, and baby sitter fees. 
 
Taking part in this study may lead to added costs that may not be covered by your insurance company. 
Please ask about any expected added costs or insurance problems. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
website at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .  You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this website. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that 
you have been injured because of taking part in this study. You can tell the doctor in person or call him/her 
at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study. You and/or your 
health plan will be charged for this treatment.  The study will not pay for medical treatment.  
 
WHAT ARE MY RIGHTS AS A STUDY PARTICIPANT? 
Taking part in this study is your choice. You may choose not to take part or not take part in the study. If you 
decide to take part in this study, you may remove yourself from 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. If you 
remove yourself from the study, we will still take care of you. We will explain what stopping the treatment 
may do and we will offer other treatments if they are available.  
 

 
 
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We will tell you about new information or changes in the study that may affect your health or your willingness 
to continue in the study.  
 
In case of injury resulting from this study, you do not lose any of you legal rights to seek payment by signing 
this form. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing data from this 
research throughout the study.  We will tell you about new information from this Board or other studies that 
may affect your health or willingness to stay in the study. 
 
 
 
WHO IS FUNDING THIS RESEARCH STUDY? 
This study is supported by Pfizer, Inc. Pfizer is a drug company that makes the drug being studied in this 
research project. Pfizer is giving money to Children's Hospital for some of the costs of the study. The results 
of the study will be reported to Pfizer. If the study shows that lorlatinib may be useful for a new purpose, 
this could benefit Pfizer financially. 
 
The Children’s Hospital Los Angeles/NANT is also providing funding for this study. 
 
Dr. Mossé at Children’s Hospital of Philadelphia, one of the principal investigators of this study, has served 
as a paid consultant to Pfizer. Her participation in this research has been reviewed and approved, subject 
to management, according to CHOP’s/NANT Conflict of Interest Policy.  
 
 
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).  
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the NCI’s Cancer Information Service at 
 
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615 
 
You may visit the NCI Web sites 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/ 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you.  At most, the website will include a 
summary of the results.  You can search this website at any time. 
 
You will get a copy of this consent form. If you want more information about this study, ask your doctor. 
 
 

 
 
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CONSENT FOR EXTRA STUDIES FOR RESEARCH  
 
The following tests are optional for all patients in the study. You may still participate in the study 
even if you do not agree to these tests. 
 
1. 
Using extra blood to look for genetic changes seen in tumor cells 
 
Initial next to YES if you agree to let researchers take almost 4 extra teaspoons (17 mL) at study entry 
and each time a disease evaluation is done)  to look at what genetic changes in your tumor can be 
seen in your blood over time before and after treatment with lorlatinib.  This blood would be drawn at 
a time when blood was being drawn for clinical purposes.  The blood will be sent to Foundation 
Medicine Inc. for analysis who is a collaborator on this study. The results of these tests will be 
confidential and not made available to you or your treating physician. 
 
Initial next to NO, if you do not want researchers to take extra blood above what is needed for 
clinical purposes. 
 
_______Yes 
_______No    
 
2. 
Comparing genetic changes between tumor leftover from an earlier procedure (diagnosis or 
second look) to relapsed neuroblastoma tumor tissue and bone marrow aspirates and 
whether these changes affect how the tumor will respond to treatment with Lorlatinib. 
 
Initial next to YES, if you agree (and if there is tumor remaining)  to let this tumor be sent to a laboratory 
so researchers can compare these samples and determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  The results 
of these tests will be confidential and not made available to you or your treating doctor. 
 
Initial next to NO if you do not want left over tumor from an earlier procedure to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely 
to respond to the drug lorlatinib. 
 
_______Yes 
_______No    
 
 
Initial next to YES, if you agree to let extra bone marrow aspirates be collected to be sent to a 
laboratory so researchers can compare these samples and determine if there are certain gene 
changes present that might make your neuroblastoma more or less likely to respond to the drug 
lorlatinib.  The results of these tests will be confidential and not made available to you or your treating 
doctor. 
 
Initial next to NO if you do not want these bone marrow aspirates collected to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely 
to respond to the drug lorlatinib. 
 
 
_______Yes      _______No   
 
 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
187 
 
 
STATEMENT OF CONSENT 
 
I have already read the information in this informed consent document. I have read all the attachments 
that were included with this informed consent document. I have asked all of my questions and I have 
gotten answers. I agree to enroll myself (my child) in this study. 
 
 
______________________________________ 
Print Patient Name 
 
 
_______________________________________ 
 
_____/_____/_____ 
Signature of Patient  
 
 
 
 
 
 
Date 
 
 
_______________________________________ 
 
_____/_____/______ 
Signature of Physician or  
 
 
 
 
 
Date 
Responsible Investigator 
 
_______________________________________ 
 
____/_____/______ 
Signature of Witness 
 
 
 
 
 
 
Date 
 
 
_______________________________________ 
 
____/_____/______ 
Signature of Translator  
 
 
 
 
 
Date 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
188 
 
 
Consent Addendum I: Tests that will be done on this study. 
 
Observation 
Before Entry 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of 
Therapy 
Physical exam including 
neurological exam 
X 
Weekly 
Start of cycle 
Start of each cycle 
X 
Routine blood tests** 
(Blood counts, electrolytes, liver, kidney 
function, , function of pancreas- 
amylase/lipase) 
X 
Weekly  
Weekly for blood 
counts and twice 
during cycle for all 
other blood tests   
Start of each cycle 
X 
Routine Blood tests** 
(Fasting cholesterol, triglycerides, 
glucose) 
X 
Every other week  
Start of cycle  
Start of each cycle  
X  
Hemoglobin A1c (HbA1c)  
X 
 
Start of cycle  
With Disease Evaluations in 
Courses 4 and 6 and after 
every 4 cycles thereafter  
X  
Pregnancy test 
(All females 10 years of age and older) 
X 
 
Start of cycle 
Start of each cycle 
 
Heart rhythm test 
(EKG)  
X 
One hour after 
day 1 treatment is 
finished 
End of cycle 
End of cycle (4,6 and every 
4th cycle thereafter) 
X 
Neuropsychological Testing  
 
Within one week 
before starting 
treatment 
End of cycle 
End of cycle 
End of cycle (4, 6 and every 
4th cycle thereafter) 
X 
Neuropsychological evaluation with 
licensed psychologist for patients 
less than 3 years of age 
Within one week 
before and up to 
one week after 
starting 
treatment 
 
End of cycle 
End of cycle 6, 10 and then 
every 8 cycles thereafter 
X 
Submit Patient Treatment Diaries 
 
X 
X 
X 
X 
Blood for Lorlatinib drug level tests 
(PK - Required) 
 
Day 1: 3 times 
Day 2: 1 time 
Day 15: 5 times 
 
 
 
Bone Marrow Aspirate (Optional) 
X 
 
With disease 
evaluation 
End of cycle (4,6, and every 
4th cycle thereafter) 
 
Blood for circulating tumor cells 
(Optional) 
X 
 
With disease 
evaluation 
End of cycle (4,6 and every 
4th cycle thereafter) 
 
Sampling of leftover tumor tissue 
(Optional) 
Leftover tumor tissue can be sent at any time during the study 
 
Tests done at Disease Evaluation 
Bone marrow aspirate and biopsy 
X 
 
Week 4 
End of cycle (4,6 and every 
4th cycle thereafter) 
X 
CT/MRI scans and/or MIBG/PET 
scans 
Blood and bone marrow for NANT 
Biology study# 
# Patients enrolled in the companion biology study may have additional samples of blood and bone marrow collected at study entry 
and with each disease evaluation time point. Please look at the biology study N04-05 consent form for more information. 
**Blood draws can be done more often if needed at the discretion of your study doctor 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
189 
 
 
Consent Addendum 2 
Certificate of Confidentiality Information 
 
NANT 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. 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
190 
 
 
APPENDIX IX:  SAMPLE ASSENT FORM COHORTS A1 AND B1 
 
NANT 2015-02:  PHASE 1 STUDY OF PF-06463922 (LORLATINIB), AN ORAL SMALL MOLECULE 
INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY 
NEUROBLASTOMA 
 
Cohorts A1 and B1:  Taking Lorlatinib only 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol  
 
INVESTIGATOR 
[Insert Name of Investigator] 
[Insert Name of Institution] 
 
[Insert Address (include City, State and Zip Code)]  
[Insert Telephone/Fax Numbers] 
[Insert Email] 
 
 
1.  Dr. _______________ is doing a research study about using other medicines to get rid of 
Neuroblastoma.  
 
2.  You have a kind of cancer called neuroblastoma. We are doing a study about this kind of cancer. It 
may be that your cancer went away for a while but has come back. Or it may be that it has never gone 
away. We are asking you to take part in a research study because doctors want to learn more about 
treating neuroblastoma using a medicine called lorlatinib to see what effects (both good and bad) this 
medicine has on patients and their cancer.  Lorlatinib is a medicine that is given by mouth either as a 
pill (tablet) or a liquid.  The doctors think that giving this drug may help get rid of neuroblastoma cancer 
cells.   
 
3. If you agree to be in this study this is what will happen: 
You will take lorlatinib by mouth every day followed by a small glass of water.   Lorlatinib is given in 
cycles that last about one month (28 days).  You can continue taking lorlatinib for as many cycles as you 
can unless there are side effects or your tumor gets worse.  Lorlatinib works differently than some of the 
other medicines you have gotten before to treat your neuroblastoma.    Before this study started, the 
doctors sent a sample of your tumor to a laboratory for testing and found out there is a change in the 
ALK gene.  The ALK gene is a gene that when it has been changed, can help your neuroblastoma tumor 
to grow.  Lorlatinib works on the ALK gene.  Researchers hope it will stop your neuroblastoma tumor 
from growing.   
 
Coming to See the Doctors: 
During and after you have finished the treatment, you will have appointments with the doctors who are 
taking care of you. This is called “Follow-Up”.  This is to see how well the treatment has worked so far. 
The doctors will want to do some special tests to find this information out. They will include; 
 
  
• 
Blood tests (we will do this twice each week to start with, and then less often).  You may need 
to fast (not eat anything and not drink anything other than water) for 8 hours before certain 
blood tests.  This will happen once per week in the first month of treatment and then just once 
per month during the rest of treatment.  
• 
A heart test called an EKG that shows the doctors your heart beat.  This is done by attaching 
wires from an EKG machine to your chest with sticky pads.  It takes less than 5 minutes to 
do this test once all the wires are attached. 
• 
MRI, CT, and MIBG Scans (special pictures of your tumor) 
• 
Bone marrow test (to look for tumor in your bone marrow) 
• 
Feel your belly, look into your eyes and ears, and listen to your heart and lungs. 
• 
Ask you and your parents a lot of questions about how you are feeling, how you are doing in 
school, and any problems you might be having.   

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
191 
 
 
o 
The doctors will have you answer questions about how you are doing using an iPad.  
This should take about 30 minutes to do.  At the same time you are using your iPad; 
your parents will also answer questions about how you are doing using pen and 
paper.  This testing will be done at the beginning then monthly to every other month 
for a year then less often after that.  Your doctor will let you know if any of these 
testing needs to be done more often. 
• 
You will come to visit your doctor every week or so to start with, then less often if everything 
is going well.  
• 
To measure the amount of medicine in your blood, we will draw 9 blood samples (about 5 
teaspoons total) over the first 2 days of treatment with lorlatinib.  We can use your central 
line to draw these blood samples.  If you don’t have a central line, you will need to have a 
needle poke or a small plastic tube placed in a vein of your hand or arm to collect these 
samples.  
 
4. When you are in a research study, sometimes good things and bad things can happen. 
Sometimes things happen to kids in research studies that may make them feel bad.  These are called 
“risks”.  Some of the risks of this study are:  
• 
You may feel lightheaded, jittery, irritable or hungry while you are fasting before certain tests  
• 
You may have swelling in your arms and legs 
• 
You may have tingling, or prickly feeling or numbness in your hands and feet 
• 
You may have a hard time concentrating, remembering things or talking to others. 
• 
You may feel tired 
• 
You may feel sick to your stomach and you may throw up 
• 
You may not feel like eating 
•   You may get diarrhea or constipation 
•   You may feel difficulty breathing  
•   You may gain weight  
• 
The treatments may not work and your tumor may grow, or it might come back again after the 
treatment has finished.  If this happens, we will try other ways to stop the tumor from growing. 
• 
You could get a different kind of cancer, this doesn’t happen often, but can happen years later. 
• 
It is possible you could die from the treatment or cancer. 
 
Not all of these things may happen to you. It’s possible that none of them will happen. Or bad things may 
happen that we don’t know about yet.  
• 
Things that happen to children in research studies that are good are called “benefits”.  Some of 
the good things for this research study could be: 
o 
This treatment might make your neuroblastoma tumor stay the same size or get smaller 
for some time. 
o 
We hope to learn more about this new treatment which could help other children with 
neuroblastoma 
 
5. We will do everything possible to keep your information private and prevent people outside of the study 
from seeing information about you.  
 
6. Please talk this over with your parents before you decide whether or not to be in this study. We will also 
ask your parents to give their permission for you to take part in this study.  But even if your parents 
say “yes” you can still decide not to do this.   
 
7. You do not have to be in this study if you don’t want to. You may stop being in this study at any time. 
Remember, being in this study is up to you.  
 
8. You can ask any questions that you have about the study. If you have a question later that you didn’t 
think of now, you can call me or ask me next time you see me.   
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
192 
 
 
o Study doctor’s phone number: __________________ 
 
9. Special Study Tests:  
You will have blood tests done to measure the amount of lorlatinib in your blood.  This blood test will 
be done 9 times over 3 days in the first course. A central line can be used to draw these blood samples.  
Otherwise you may need to have a needle poke or a small plastic tube placed in a vein of your hand or 
arm for these samples. 
 
There are extra tests on this study that are optional meaning that you can say no to doing these tests 
and still be part of the main study.  Please discuss this with your family. These extra tests are done for 
research only so the results won’t be told to your doctor or to you. 
 
#1:   
Almost 4 teaspoons of extra blood will be taken at the same time blood will be drawn as part 
of your  normal neuroblastoma care.  This would be done when you start the study and then 
every time after when you have tests and scans to look at how your tumor is doing (called a 
disease evaluation). 
 
 
#2:  
The doctors will compare old and new tumor samples and bone marrow aspirates collected 
from you as part of your normal neuroblastoma care.  They will be looking at changes in the 
ALK gene in these tumor samples. 
 
 
 
Signing your name at the bottom means that you agree to be in this study.   You and your parents will be 
given a copy of this form after you have signed it. 
 
Name of Patient: _________________________ 
 
 
 
 
 
 
 
 
 
_______ Yes, I want to be in the study. 
 
______     No, I do not want to be in the study. 
 
________________________________________ 
_____________________ 
Signature of Patient 
 
 
 
 
 
Date 
 
________________________________________ 
_____________________ 
Name of Physician or Responsible Investigator 
 
Date 
 
_____________________________________  
______________________ 
Signature of Physician or Responsible Investigator  
Date  
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
193 
 
 
APPENDIX X:  SAMPLE ASSENT FORM COHORT A2 
 
NANT 2015-02:  PHASE 1 STUDY OF PF-06463922 (LORLATINIB), AN ORAL SMALL MOLECULE 
INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY 
NEUROBLASTOMA 
 
Cohort A2:  Taking Lorlatinib only 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol  
 
INVESTIGATOR 
[Insert Name of Investigator] 
[Insert Name of Institution] 
 
[Insert Address (include City, State and Zip Code)]  
[Insert Telephone/Fax Numbers] 
[Insert Email] 
 
 
1. Dr. _______________ is doing a research study about using other medicines to get rid of 
Neuroblastoma.  
 
2. You have a kind of cancer called neuroblastoma. We are doing a study about this kind of cancer. 
It may be that your cancer went away for a while but has come back. Or it may be that it has never 
gone away. We are asking you to take part in a research study because doctors want to learn more 
about treating neuroblastoma using a medicine called lorlatinib to see what effects (both good and 
bad) this medicine has on patients and their cancer.  Lorlatinib is a medicine that is given by mouth 
either as a pill (tablet) or a liquid.  The doctors think that giving this drug may help get rid of 
neuroblastoma cancer cells.   
 
3. If you agree to be in this study this is what will happen: 
You will take lorlatinib by mouth every day followed by a small glass of water.   Lorlatinib is given in 
cycles that last about one month (28 days).  You can continue taking lorlatinib for as many cycles as 
you can unless there are side effects or your tumor gets worse.  Lorlatinib works differently than some 
of the other medicines you have gotten before to treat your neuroblastoma.    Before this study started, 
the doctors sent a sample of your tumor to a laboratory for testing and found out there is a change in 
the ALK gene.  The ALK gene is a gene that when it has been changed, can help your neuroblastoma 
tumor to grow.  Lorlatinib works on the ALK gene.  Researchers hope it will stop your neuroblastoma 
tumor from growing.   
 
Coming to See the Doctors: 
During and after you have finished the treatment, you will have appointments with the doctors who 
are taking care of you. This is called “Follow-Up”.  This is to see how well the treatment has worked 
so far. The doctors will want to do some special tests to find this information out. They will include; 
 
  
• 
Blood tests (we will do this twice each week to start with, and then less often).  You may need 
to fast (not eat anything and not drink anything other than water) for 8  hours before certain 
blood tests.  This will happen once per week in the first month of treatment and then just once 
per month during the rest of treatment.  
• 
A heart test called an EKG that shows the doctors your heart beat.  This is done by attaching 
wires from an EKG machine to your chest with sticky pads.  It takes less than 5 minutes to 
do this test once all the wires are attached. 
• 
MRI, CT, and MIBG Scans (special pictures of your tumor) 
• 
Bone marrow test (to look for tumor in your bone marrow) 
• 
Feel your belly, look into your eyes and ears, and listen to your heart and lungs. 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
194 
 
 
• 
Ask you and your parents a lot of questions about how you are feeling, how you are doing in 
school, and any problems you might be having.   
o 
The doctors will have you answer questions about how you are doing using an iPad.  
This should take about 30 minutes to do.  At the same time you are using your iPad; 
your parents will also answer questions about how you are doing using pen and 
paper.  This testing will be done at the beginning then monthly to every other month 
for a year then less often after that.  Your doctor will let you know if any of these 
testing needs to be done more often. 
• 
You will come to visit your doctor every week or so to start with, then less often if everything 
is going well.  
• 
To measure the amount of medicine in your blood, we will draw 9 blood samples (about 5 
teaspoons total) over the first 2 days of treatment with lorlatinib.  We can use your central 
line to draw these blood samples.  If you don’t have a central line, you will need to have a 
needle poke or a small plastic tube placed in a vein of your hand or arm to collect these 
samples.  
 
4. When you are in a research study, sometimes good things and bad things can happen. 
Sometimes things happen to kids in research studies that may make them feel bad.  These are called 
“risks”.  Some of the risks of this study are:  
a. You may feel lightheaded, jittery, irritable or hungry while you are fasting before certain 
tests  
b. You may have swelling in your arms and legs 
c. You may have tingling, or prickly feeling or numbness in your hands and feet 
d. You may have a hard time concentrating, remembering things or talking to others. 
e. You may feel tired 
f. 
You may feel sick to your stomach and you may throw up 
g. You may not feel like eating 
h. You may get diarrhea or constipation 
i. 
You may feel difficulty breathing 
j. 
You may gain weight 
k. The treatments may not work and your tumor may grow, or it might come back again 
after the treatment has finished.  If this happens, we will try other ways to stop the tumor 
from growing. 
l. 
You could get a different kind of cancer, this doesn’t happen often, but can happen years 
later. 
m. It is possible you could die from the treatment or cancer. 
 
Not all of these things may happen to you. It’s possible that none of them will happen. Or bad things 
may happen that we don’t know about yet.  
• 
Things that happen to children in research studies that are good are called “benefits”.  Some of 
the good things for this research study could be: 
o 
This treatment might make your neuroblastoma tumor stay the same size or get smaller 
for some time. 
o 
We hope to learn more about this new treatment which could help other children with 
neuroblastoma 
 
5. We will do everything possible to keep your information private and prevent people outside of the 
study from seeing information about you.  
 
6. Please talk this over with your parents before you decide whether or not to be in this study. We will 
also ask your parents to give their permission for you to take part in this study.  But even if your 
parents say “yes” you can still decide not to do this.   
 
7. You do not have to be in this study if you don’t want to. You may stop being in this study at any 
time. Remember, being in this study is up to you.  

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
195 
 
 
 
8. You can ask any questions that you have about the study. If you have a question later that you 
didn’t think of now, you can call me or ask me next time you see me.   
o Study doctor’s phone number: __________________ 
 
9. Special Study Tests:  
You will have blood tests done to measure the amount of lorlatinib in your blood.  This blood test will 
be done 9 times over the 3 days in the first course.   A central line can be used to draw these blood 
samples.  Otherwise you may need to have a needle poke or a small plastic tube placed in a vein of 
your hand or arm for these samples. 
 
There are extra tests on this study that are optional meaning that you can say no to doing these tests 
and still be part of the main study.   These extra tests are done for research only so the results won’t 
be told to your doctor or to you. 
 
#1:   
Almost 4 teaspoons of extra blood will be taken at the same time blood will be drawn as part 
of your  normal neuroblastoma care.  Please discuss this with your family. This would be done 
when you start the study and then every time after when you have tests and scans to look at 
how your tumor is doing (called a disease evaluation). 
 
#2:  
The doctors will compare old and new tumor samples and bone marrow aspirates collected 
from you as part of your normal neuroblastoma care.  They will be looking at changes in the 
ALK gene in these tumor samples. 
 
 
Signing your name at the bottom means that you agree to be in this study.   You and your parents will be 
given a copy of this form after you have signed it. 
 
Name of Patient: _________________________ 
 
 
 
_______ Yes, I want to be in the study. 
______     No, I do not want to be in the study. 
 
________________________________________ 
_____________________ 
Signature of Patient 
 
 
 
 
 
Date 
 
________________________________________ 
_____________________ 
Name of Physician or Responsible Investigator 
 
Date 
 
_____________________________________  
______________________ 
Signature of Physician or  
 
 
 
 
Date  
Responsible Investigator 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
196 
 
 
APPENDIX XI:  SAMPLE ASSENT FORM COHORT B2 
 
NANT 2015-02:  PHASE 1 STUDY OF PF-06463922 (LORLATINIB), AN ORAL SMALL MOLECULE 
INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY 
NEUROBLASTOMA 
 
Cohort B2:  Taking Lorlatinib combined with chemotherapy (cyclophosphamide/topotecan) 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol  
 
INVESTIGATOR 
[Insert Name of Investigator] 
[Insert Name of Institution] 
 
[Insert Address (include City, State and Zip Code)]  
[Insert Telephone/Fax Numbers] 
[Insert Email] 
 
 
1.  Dr. _______________ is doing a research study about using other medicines to get rid of 
Neuroblastoma.  
 
2.  You have a kind of cancer called neuroblastoma. We are doing a study about this kind of cancer. It 
may be that your cancer went away for a while but has come back. Or it may be that it has never gone 
away. We are asking you to take part in a research study because doctors want to learn more about 
treating neuroblastoma using three experimental medicines called lorlatinib, cyclophosphamide 
and topotecan  and to see what effects (both good and bad) these medicines has on patients and 
their cancer.  Lorlatinib is a medicine that is given by mouth either as a pill (tablet) or a liquid.  
Cyclophosphamide and topotecan are medicines that are given into the bloodstream either through 
your central line or a small tube placed in a vein in your hand or arm.  The doctors think that giving 
these three drugs together may help get rid of neuroblastoma cancer cells.   
 
3. If you agree to be in this study this is what will happen: 
 
The medicines will be given in cycles that each last about one month (28 days).  Your doctor will explain 
the schedule for each cycle to you and your parents.  You can continue to get this treatment unless you 
have bad side effects or your tumor gets worse.  These medicines work differently than some of the 
other medicines you have gotten before to treat your neuroblastoma.  
 
Before this study started, the doctors sent a sample of your tumor to a laboratory for testing and found 
out there is a change in the ALK gene.  The ALK gene is a gene that when it has been changed, can 
help your neuroblastoma tumor to grow.  Lorlatinib works on the ALK gene.  Researchers hope it will 
stop your neuroblastoma tumor from growing when used together the chemotherapy medinces 
cyclophosphamide and topotecan.   
 
Lorlatinib: 
You will take lorlatinib by mouth every day followed by a small glass of water.    
 
Cyclophosphamide and topotecan: 
You will take cyclophosphamide and topotecan by I.V. once a day for the first 5 days of every cycle. You 
will be in the clinic on those days.  You do not need to be in the hospital to get these chemotherapy 
medicines. 
 
 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
197 
 
 
Other medicines (not chemotherapy): 
You will need to take Neupogen (given once a day as an injection) or Neulasta (given once each 
 
cycle as an injection).  These medicines are given to help your normal blood cells get better after 
 
getting chemotherapy medicines like cyclophosphamide and topotecan. 
 
Coming to See the Doctors: 
During and after you have finished the treatment, you will have appointments with the doctors who are 
taking care of you. This is called “Follow-Up”.  This is to see how well the treatment has worked so far. 
The doctors will want to do some special tests to find this information out. They will include; 
 
  
• 
Blood tests (we will do this twice each week to start with, and then less often).  You may need 
to fast (not eat anything and not drink anything other than water) for 8 hours before certain 
blood tests.  This will happen once per week in the first month of treatment and then just once 
per month during the rest of treatment.  
• 
A heart test called an EKG that shows the doctors your heart beat.  This is done by attaching 
wires from an EKG machine to your chest with sticky pads.  It takes less than 5 minutes to 
do this test once all the wires are attached. 
• 
MRI, CT, and MIBG Scans (special pictures of your tumor) 
• 
Bone marrow test (to look for tumor in your bone marrow) 
• 
Feel your belly, look into your eyes and ears, and listen to your heart and lungs. 
• 
Ask you and your parents a lot of questions about how you are feeling, how you are doing in 
school, and any problems you might be having.   
o 
The doctors will have you answer questions about how you are doing using an iPad.  
This should take about 30 minutes to do.  At the same time you are using your iPad; 
your parents will also answer questions about how you are doing using pen and 
paper.  This testing will be done at the beginning then monthly to every other month 
for a year then less often after that.  Your doctor will let you know if any of these 
testing needs to be done more often. 
• 
You will come to visit your doctor every week or so to start with, then less often if everything 
is going well.  
• 
To measure the amount of medicine in your blood, we will draw 9 blood samples (about 5 
teaspoons total) over the first 2 days of treatment with lorlatinib.  We can use your central 
line to draw these blood samples.  If you don’t have a central line, you will need to have a 
needle poke or a small plastic tube placed in a vein of your hand or arm to collect these 
samples.  
 
4. When you are in a research study, sometimes good things and bad things can happen. 
Sometimes things happened to children in research studies that may make them feel bad.  These are 
called “risks”.  Some of the risks of this study are:  
• 
You may feel lightheaded, jittery, irritable or hungry while you are fasting before certain tests  
• 
You may have swelling in your arms and legs 
• 
You may have tingling, or prickly feeling or numbness in your hands and feet 
• 
You may have a hard time concentrating, remembering things or talking to others. 
• 
You may feel tired 
• 
You may feel sick to your stomach and you may throw up  
• 
You may not feel like eating  
• You might have a fever and maybe an infection where you will need to be in the hospital to get 
medicines to treat the infection.  You may feel tired and weak and need a blood transfusion 
or you may get bruises or have bleeding (most often a nosebleed) and need a platelet 
transfusion. 
• You may get sores in your mouth that makes it difficult to eat and drink.  If this happens, you 
may need some pain medicines and you may need to stay in the hospital. 
• You may get diarrhea or constipation. 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
198 
 
 
• You may feel difficulty breathing 
• You may gain weight 
• 
The treatments may not work, and your tumor may grow, or it might come back again after the 
treatment has finished. If this happens we will try other ways to stop the tumor from growing  
• 
You could get a different kind of cancer, this doesn’t happen often, but can happen years later 
• 
It is possible that you could die from the treatment or cancer  
 
Not all of these things may happen to you. It’s possible that none of them will happen. Or bad things 
may happen that we don’t know about yet.  
 
Things that happen to children in research studies that are good are called “benefits”.  Some of the 
good things for this research study could be: 
• 
This treatment might make your neuroblastoma tumor stay the same size or get smaller for some 
time. 
• 
We hope to learn more about this new treatment which could help other children with 
neuroblastoma 
 
5. We will do everything possible to keep your information private and prevent people outside of the study 
from seeing information about you.  
 
6. Please talk this over with your parents before you decide whether or not to be in this study. We will also 
ask your parents to give their permission for you to take part in this study.  But even if your parents 
say “yes” you can still decide not to do this.   
 
7. You do not have to be in this study if you don’t want to. You may stop being in this study at any time. 
Remember, being in this study is up to you.  
 
8. You can ask any questions that you have about the study. If you have a question later that you didn’t 
think of now, you can call me or ask me next time you see me.   
 
o Study doctor’s phone number: __________________ 
 
9. Special Study Tests:  
You will have blood tests done to measure the amount of lorlatinib in your blood.  This blood test will 
be done 9 times over 3 days in the first course.   A central line can be used to draw these blood samples.  
Otherwise you may need to have a needle poke or a small plastic tube placed in a vein of your hand or 
arm for these samples. 
 
There are extra tests on this study that are optional meaning that you can say no to doing these tests 
and still be part of the main study. Please discuss this with your family.  These extra tests are done for 
research only so the results won’t be told to your doctor or to you. 
 
#1:   
Almost 4 teaspoons of extra blood will be taken at the same time blood will be drawn as part 
of your  normal neuroblastoma care.  This would be done when you start the study and then 
every time after when you have tests and scans to look at how your tumor is doing (called a 
disease evaluation). 
 
 
#2:  
The doctors will compare old and new tumor samples and bone marrow aspirates collected 
from you as part of your normal neuroblastoma care.  They will be looking at changes in the 
ALK gene in these tumor samples. 
 
 
 
 

 
 
NANT 2015-02 Amendment 11A v. 05-06-2022 
 
199 
 
 
 
 
Signing your name at the bottom means that you agree to be in this study.   You and your parents will be 
given a copy of this form after you have signed it. 
 
 
Name of Patient: _________________________ 
 
 
 
 
 
 
 
 
 
 
_______ Yes, I want to be in the study. 
 
______     No, I do not want to be in the study. 
 
 
 
________________________________________ 
_____________________ 
Signature of Patient 
 
 
 
 
 
Date 
 
 
________________________________________ 
_____________________ 
Name of Physician or Responsible Investigator 
 
Date 
 
 
_____________________________________  
______________________ 
Signature of Physician or  
 
 
 
 
Date  
Responsible Investigator 
 
 
 
 

APPENDIX VI: DOSE ESCALATION AND EXPANSION COHORT (A1 & B1) SAMPLE CONSENT 
 
NANT 2015-02:  PHASE 1 STUDY OF LORLATINIB (PF-06463922), AN ORAL SMALL MOLECULE 
INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY 
NEUROBLASTOMA 
 
PHASE 1 DOSE ESCALATION & EXPANSION COHORT (A1 & B1): FOR PATIENTS ONE YEAR OF 
AGE UP TO 18 YEARS OF AGE  
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol. 
 
The word “you” used throughout this document refers to you or your child. 
 
WHAT IS THIS STUDY ABOUT? 
This study is a clinical trial, a type of research study. Clinical trials include only patients who choose to take 
part. Please take your time to make your decision about participating. You may discuss your decision with 
your friends, family, and health care team. If you have any questions, you may ask your doctor. 
 
You are being asked to participate in this study because you have a kind of cancer called neuroblastoma. 
It may be that your cancer went away for a while but has grown back (relapsed) or it may be that it has 
never gone away (persistent or resistant tumor) after standard treatment. Standard treatment may have 
included chemotherapy, surgery, radiation therapy, high-dose chemotherapy with a stem cell transplant 
and/or immunotherapy. 
 
WHY IS THIS STUDY BEING DONE? 
 
The purposes of this study are: 
 
• 
To find the highest safe dose of lorlatinib that can be given to children and adolescents with 
refractory or relapsed neuroblastoma without causing severe side effects. 
 
• 
To learn about the side effects of the drug  lorlatinib given at different dose levels to children and 
adolescents 1-18 years of age. 
 
• 
To determine if your tumor gets smaller after treatment with lorlatinib. 
 
• 
To measure the levels of lorlatinib in the blood at different dose levels. 
 
• 
To look at genetic changes in tumor DNA found in the blood during treatment with lorlatinib. 
 
• 
To look at genetic changes in tumor tissue to see if they affect response to lorlatinib. 
 
• 
To describe the amount of neuroblastoma tumor found in the blood and bone marrow by testing 
samples with a new test (called NB5 assay). 
 
The research is being done because: 
Currently there is no known effective treatment for your type of cancer.  We are testing new experimental 
drugs such as lorlatinib in the hopes of finding a drug that may be effective against neuroblastoma tumors 
that have come back (relapsed) or that have never gone away (persistent/refractory) after treatment with 
standard therapy.  
 
This study involves the use of an experimental drug called lorlatinib.  In laboratory testing, lorlatinib blocks the 
Anaplastic Lymphoma Kinase (ALK). ALK may be important in the growth of certain types of cancer cells, 
such as neuroblastoma.  Lorlatinib is considered experimental because it has not been proven to work in a 

situation like yours.  Lorlatinib has been approved by the United States Food and Drug Administration (FDA) 
to treat adults with non-small cell lung cancer, a different cancer than yours. It is not approved for 
neuroblastoma.  Lorlatinib has been used only in a small number of adults so there is a lot we do not know 
about it yet.  Lorlatinib has not previously been used in children and adolescents not enrolled on this study.  
This study is called a phase 1 study because the goal is to find the highest dose of lorlatinib that we can 
give safely.  Once we have found out the highest dose of lorlatinib that can be given safely, we will treat 
more children and adolescents with neuroblastoma with this Lorlatinib dose.   
 
All patients enrolled on this phase 1 study have been previously tested and are known to have a defect in 
the ALK gene in their tumor before they start treatment.  You or your doctor should have the results of this 
test before enrolling on this study.     
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
There will be about 60-75 patients enrolling on the 4 study cohorts. You have been given this consent 
because the planned enrollment is on cohort A1 or B1.     When you join the study, you will be assigned a 
certain lorlatinib dose.  This study will test up to five lorlatinib doses in groups of 3-6 patients.  The starting 
lorlatinib dose for the first group of patients was about 25% lower than what was given to adults who 
received lorlatinib without bad side effects.  If this is tolerated without serious side effects, then the lorlatinib 
dose will be increased in groups of 3-6 patients until the fifth dose level or if serious side effects are seen.  
At that point, investigators will have found the highest dose of lorlatinib that can be given without bad side 
effects.  This part of the trial is called cohort A1. 
 
  
Once the maximum tolerated dose is determined, another group of 6 patients will be enrolled and treated 
at this dose of lorlatinib, known as the dose expansion part of the study (Cohort B1).  The purpose of the 
dose expansion part of the study is to gather more information about side effects seen in patients treated 
at the maximum tolerated dose of lorlatinib. The dose expansion cohort (Cohort B1) will not enroll patients 
until the dose escalation part of the study (Cohort A1) is completed and the highest dose of lorlatinib that 
can be given safely without serious side effects is found. 
 
WHAT WILL HAPPEN TO ME IF I TAKE PART IN THIS STUDY? 
 
Before You Begin the Study  
Your doctor will have previously sent your tumor for genetic testing and these results showed your tumor 
has a defect in the ALK gene which allows you to be considered for participation in this study (Cohorts A1 
and B1). 
 
You will need to have the following exams, tests or procedures to find out if you can take part in the study. 
Most of these exams, tests or procedures are part of regular cancer care and may be done even if you do 
not join the study. These tests will also be done at various times throughout the study and at the end of the 
study.  The purpose of these tests is to see how well the treatment works and to measure the status of your 
neuroblastoma.   If you have had some of them recently, they may not need to be repeated. This will be up 
to your doctor. 
 
A medical history & physical exam 
Bone marrow tests3 to check your tumor 
Blood tests1 
Various scans4 to check your tumor 
Pregnancy test (urine or blood)2 
Electrocardiogram (EKG) to check the heart rhythm5 
 
Neuropsychological testing6 
1Some blood tests (cholesterol and fat digestion [triglycerides]) may need to be done on an empty stomach, 
so you cannot eat or drink anything other than water for 8 hours before these tests are done (called fasting).   
Your doctor or nurse will tell you if it is necessary for you to fast before these blood tests are done. 
 
 

2If you are a female at least 10 years old or who could have children, you will have a pregnancy test done 
by the doctor the week before starting treatment and then before each cycle of treatment begins.  Both you 
and your parent/legal guardian will be informed of a positive pregnancy test. All men and women who could 
have children must either agree to practice abstinence from heterosexual intercourse or use two effective 
methods of birth control for as long as they participate in this study.  
 
3Bone marrow tests are done by inserting a needle into the hip bone to remove the marrow which is inside 
the bone. 
 
4Various scans are done for diagnosis and checking the response of the tumor to treatment. These may 
include CT and /or MRI scans and MIBG or PET scans. We will recommend scans specific for your case 
and we will answer your questions about these scans. 
 
5Electrocardiogram (EKG) to document your heart rhythm before beginning lorlatinib treatment.  
 
6 Central nervous system effects (speech, memory and mood changes) were seen in previous studies 
treating adults with lorlatinib. Neuropsychological testing will be done within one week of starting treatment 
and at different times during this study to monitor for any changes in thinking skills, behavior and mood.   
Please see the section on Neuropsychological testing below in “During the Study” for more details on what 
tests are done and when they are done during this study. 
 
During the Study   
If the exams, tests and procedures show that you can be in the study, and you choose to take part, lorlatinib 
will be given for 28 days.  This entire period is called a cycle with each treatment cycle being 28 days long.  
You may continue to take lorlatinib for an unlimited number of cycles unless you develop serious side effects 
or your tumor worsens. 
 
Lorlatinib will be given by mouth once a day followed by a small glass of water.  If you vomit lorlatinib within 
20 minutes of taking the dose for the day, that dose can be repeated.  This is the only time a dose of 
lorlatinib can be repeated.  
 
Lorlatinib will be available as a tablet. If you are unable to swallow the tablets whole, you will be instructed 
on how to make a liquid lorlatinib solution at home by mixing the lorlatinib tablets with water and a flavoring 
agent (Ora-Plus®).  Your nurse or doctor will help you decide what is best for you and will make sure you 
have the proper directions for taking this medication. 
 
You will be given a patient diary at the beginning of each cycle of lorlatinib.  Use the diary to record the date 
and time you take the drug, all vomited and missed doses, side effects that you experience and any other 
medications and supplements you are taking.  The diary should be returned to clinic along with the 
medication bottle (even if it is empty) weekly during cycle 1 and then after each treatment cycle of lorlatinib.  
This will help us to know how much of the drug you take and how it made you feel. 
 
During the study you will have tests and procedures done to check for side effects from taking lorlatinib and 
to see how your tumor is doing.  Many of these tests are part of regular cancer care but you may have them 
done more often because you are on the study: 
One Treatment Cycle   
(Cohort A1: dose escalation group and Cohort B1: dose expansion group) 
Week 1 
Week 2 
Week 3 
Week 4 
Days 1 – 7 
Days 8 - 14 
Days 15 - 21 
Days 22 - 28 
 
Lorlatinib once a day 
 

 
 
Physical exam 
Electrocardiogram (EKG) to test heart rhythm 3 
Blood tests 1 
Bone marrow tests & various scans (CT/MRI, MIBG or PET) to 
check your tumor 4 
Pregnancy test (urine or blood) 2 
 Neuropsychological testing5 
 
1 Some blood tests (cholesterol and fat digestion) may be done on an empty stomach, so patients cannot 
eat or drink anything other than water for 8-10 hours before these tests are done.   
 
2 A urine or blood pregnancy test will be done before each treatment cycle begins if you are a female at 
least 10 years old or who could have children.  Both you and your parent/legal guardian will be informed of 
a positive pregnancy test.  All men and women who could have children must continue to practice 
abstinence from heterosexual intercourse or use two effective methods of birth control for as long as they 
participate in this study.  
3 Electrocardiogram (EKG) done before starting study treatment will be repeated at certain times during the 
study to document if lorlatinib treatment has any effect on heart rhythm. 
 
4 Bone marrow tests and various scans are done for checking the response of your tumor to treatment.  
These tests will be done at certain times during the study to look at response to lorlatinib and check that 
your tumor has not gotten worse. 
 
5 Neuropsychological Testing 
Neuropsychological evaluations try to understand how changes in the health of the brain may affect 
behavior or mood and how well a person is able to pay attention, remember things or solve problems.  Since 
effects on speech, memory and mood were seen in a small number of adults receiving lorlatinib, 
neuropsychological testing will be done to monitor for changes in thinking skills, behavior and mood at 
different times during this study.  A table at the end of the consent lists how often neuropsychological testing 
will be done during the study.  Testing methods are based on the age of the patient and include 
computerized tests using an iPad, written questionnaires and evaluations by a licensed psychologist.  
Parents or legal guardians of patients less than 18 years of age will also participate by completing written 
questionnaires at the same time their child is being tested.   
 
If the testing results show areas of concern, you may be given more frequent testing as well as referrals for 
other care if needed.  During testing, patients may skip questions that are stressful and may stop taking the 
tests at any time.  Testing can be done as part of the clinic visit.  You will need to talk with your doctor and 
nurse about scheduling to do these tests at times that are workable for you and your child. 
 
• 
All patients 3 years of age and older will do computerized tests using an iPad.  While the patient is 
taking these tests, the patient’s parent or legal guardian will complete written questionnaires about 
the patient’s mood and emotions, behavior, daily living/functional skills and social skills with others.  
The parent/legal guardian can be in the same room during the testing but they cannot help their 
child with their tests.   
• 
Patients 18 years of age will complete computerized tests using an iPad and their own written 
questionnaires.  Parents/Legal guardians do not have testing to do with patients of this age. 
• 
Patients under 3 years of age will have an evaluation of overall functioning including language, 
motor and cognitive development done by a licensed psychologist.  This testing will take 60 to 90 
minutes to complete.  Parents/legal guardians will also complete written questionnaires at the same 
time. 
 
 
 

 
Patient age at 
testing in years 
Testing being done 
Length of testing time  
for Patients 
Length of testing time for 
Parents/legal guardians 
1 
Patient: licensed psychologist 
Parent/legal guardian: written 
questionnaires 
~ 60 - 90 minutes 
~ 20 minutes 
2 
~ 50 minutes 
3 - 5 
Patient: computerized tests using an 
iPad 
Parent/legal guardian: written 
questionnaires 
~ 10 minutes 
~ 50 minutes 
6 
~ 30 – 40 minutes 
~ 50 minutes 
7 - 9 
~ 30 – 40 minutes 
~ 50 - 55 minutes 
10 - 17 
~ 35 – 45 minutes 
~ 50 - 55 minutes 
18 
Patient: computerized tests using an 
iPad and written questionnaires 
~ 80 – 90 minutes 
NA 
 
NANT Biology Study (NANT 2004-05) 
If you choose to participate in this research, you will also be asked to join a companion NANT biology study 
to collect blood, bone marrow and tumor tissue (if available) and reports from radiology scans from patients 
with neuroblastoma. The biology study also provides a place (called NANT biorepository) where any leftover 
samples of tumor tissue or bone marrow and blood collected on this study could be transferred and stored. 
While you will be asked to join the Biology Study (NANT 2004-05), the decision to store/bank any leftover 
samples is optional and will not affect your ability to participate in this treatment study with Lorlatinib.  Your 
doctor will talk with you in detail about the NANT biology study and have you sign a separate consent form. 
 
Additional Tests in this Study 
We would like to do some extra tests called pharmacokinetic studies and biologic studies.  These tests will 
help us learn more about lorlatinib and may help children and adolescents 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 meaning you can decide whether you 
want to do them or not.  
 
Pharmacokinetic Studies: Determining Blood Levels of Lorlatinib – Required  
During this study blood samples will be collected to determine how much lorlatinib is in your blood (called 
pharmacokinetics). About 3mL (just over half a teaspoon) of blood will be drawn with each sample.  A total of 
9 blood samples will be obtained over 3 separate days during course 1 (Day 1, Day 2 and Day 15).  The total 
amount of blood drawn for testing will be about 27 mL (almost 5 ½ teaspoons). If you have a central line (such 
as a port or a Broviac) these samples can be drawn through that line or through a small tube placed in a vein 
in your hand or arm.  This amount of blood is considered safe to donate. Samples will be sent to a commercial 
laboratory contracted to perform these tests for the study. These samples will be the property of Pfizer and 
Pfizer may also use the PK Biological Samples for evaluation of the bioanalytical method. 
 
Other Biology Research Tests in this Study - Optional 
You will be asked if you want to participate in 3 optional research tests.  You can decide not to let the doctors 
do these tests and still be able to be treated as part of this study.  There are checkboxes at end of this form 
to mark whether you are willing to participate in these voluntary studies. The results of these research tests 
will not be shared with you or become part of your medical record.  These results would also not be used to 
make decisions about your care while enrolled on this study.     
 
 
 
 
 
 

• 
Using extra blood to look for genetic changes seen in tumor cells. 
Tumor cells often release small pieces of DNA into the blood stream where it can be detected by 
sensitive tests.  For this study, researchers would like to take almost 4 additional teaspoons of blood 
(17mL) at study entry and at each time a disease evaluation is done (after cycle 2, 4, 6 and then 
every 4th cycle after that) to look at what genetic changes in your tumor can be seen in your blood 
over time. The blood will be sent to a commercial laboratory for genetic testing.    
 
• 
Comparing genetic changes between leftover tumor from a surgical procedure prior to tumor 
relapse (at diagnosis or when you had surgery done after diagnosis) to relapsed 
neuroblastoma tumor tissue and bone marrow aspirates and whether these changes affect 
how the tumor will respond to treatment with Lorlatinib. 
 Researchers would like to look at tumor tissue to determine if there are certain gene changes  
 present that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.   
 These tests would be done on tumor tissue remaining from diagnosis, or any previous surgery  
 where tumor tissue was removed (removal of primary tumor or removal of tumor at a relapse) in  
the past. The tissue and bone marrow aspirates will be sent to a research laboratory at Children’s 
Hospital of Philadelphia for testing.   
 
When You Have Finished Treatment with Lorlatinib  
After you stop treatment on this study, you will continue to have tests and scans done (listed below) to 
measure how much tumor is left. If test results show you have abnormal organ function, tests are 
recommended by the study to be repeated monthly until test results are stable or normal. You doctor will 
tell you how often these tests and evaluations will be done. 
 
Medical Tests after the Study: 
 
Physical exam  
Neuropsychological testing1 
Blood tests 
Bone marrow tests & various scans to check your tumor2 
Electrocardiogram 
(EKG) 
to 
check the heart rhythm3 
 
 
1The same neuropsychological testing and evaluation done before starting study treatment will be done at 
the end of treatment with lorlatinib.  The need for any further testing after this will be up to your doctor. 
 
2Bone marrow tests and various scans (CT/MRI, MIBG or PET) are done for checking the response of your 
tumor to treatment.  These tests will be done at the end of a course and at certain times following treatment 
to monitor your tumor status. 
 
3 Electrocardiogram (EKG) done at the end of the study to document if lorlatinib treatment has any effect 
on heart rhythm.  
 
A table detailing the tests and procedures required before, during and after the study has been attached to 
the end of this consent (Consent Addendum 1). 
 
HOW LONG WILL I BE ON THIS STUDY?  
You can get an unlimited number of treatment cycles with lorlatinib as long as you are not having bad side 
effects and as long as your tumor is not getting worse.   
 
After you stop treatment, you will continue to have tests and scans done to measure how much tumor is left. 
Your doctor will tell you how often these tests will be done. Researchers will continue to collect information 
about you for a lifetime. Information will be collected about whether you are still alive; whether your tumor has 
grown back and at what sites in the body; whether you have developed any side effects from the treatment; 

or whether you have developed any additional cancer. Your doctor will give the researchers this information 
at regular intervals. 
 
CAN I STOP BEING IN THE STUDY? 
Yes. If you are thinking about stopping your participation on this study, you should talk to your doctor before 
making a final decision so he/she can tell you how to do this safely.  
 
Your doctor may also stop you from taking part in this study at any time if he/she believes it is in your best 
interest; if you do not follow study rules; or if the study is stopped. 
 
WHAT ARE THE RISKS OF THE STUDY? 
This is a Phase 1 study.  A Phase 1 study looks at how common and serious side effects can be for each 
patient at a specific dose of a drug. In a Phase 1 study, some patients may have very serious side effects 
and could die as a result of these side effects. You may be one of those patients who have serious side 
effects as a result of participating in this Phase 1 study.  
 
In this study, researchers will be looking at side effects seen in patients taking different doses of lorlatinib. 
Since subjects will be assigned to different dose levels of lorlatinib, some subjects may receive doses that 
are too small to be effective while others may receive higher doses that may cause increased side effects.  
 
Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know 
all the side effects that may happen. Side effects may be mild or very serious. Other drugs may be given 
to make side effects less serious and more comfortable (such as for nausea, headache or reaction to 
lorlatinib). Many side effects go away soon after you stop taking the study medications but it is always 
possible that side effects can be serious, long lasting or may never go away. There is also a risk of death. 
Patients are watched carefully and treatment will be stopped if bad side effects develop. There may also 
be risks we do not know about. You should talk to your doctor about any side effects that you have while 
taking part in this study.  
 

While on the study, you are at risk for the side effects listed below: 
 
Possible Risks of Lorlatinib 
 
The following side effects are considered to be related to lorlatinib have been reported:  
Very Common  
(may affect 10 or more in 100 people) 
Common 
(may affect from 1 up to less than 10 in 100 people) 
• 
Increase in cholesterol and triglycerides 
(fats in your blood)  
• 
Effects on mood (for example, irritability 
and mood swings)  
• 
Effects on memory (for example, 
confusion, memory loss and disturbance 
of attention)  
• 
Effects on the peripheral nerves which are 
those outside of the brain and spinal cord, 
including tingling, numbness or pain in 
hands and feet)  
• 
Changes in vision (including double 
vision, perceived flashes or floaters of 
light, light intolerance, vision blurred, 
vision sharpness reduced and visual 
impairment) 
• 
Hypertension  
• 
Diarrhea  
• 
Constipation  
• 
Joint pain  
• 
Build-up of fluid in the body or extremities 
causing swelling (edema)  
• 
Fatigue (feeling tired and exhausted)  
• 
Increase in body weight 
• 
Increase in blood sugar levels 
• 
Hallucination and loss of contact with 
reality 
• 
Changes in mental status  
• 
Changes in speech (for example, slow 
speech or slurred speech) 
• 
Inflammation of the lungs (pneumonitis) 
which can cause shortness of breath and 
difficulty breathing. If severe, this can be 
life threatening.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

The following events have also been reported in patients while they were taking lorlatinib, although the 
relationship to lorlatinib is uncertain:  
 
Very common (may affect 10 or more in 100 people) 
• 
Abnormalities in blood tests that may indicate liver damage 
• 
Abnormal pancreas tests 
• 
Decrease in hemoglobin in the blood that can cause weakness 
• 
Headache 
• 
Muscle pain 
• 
Difficulty sleeping 
• 
Rash 
 
Common (may affect from 1 up to less than 10 in 100 people) 
• 
Decrease of ejection fraction of the heart which may indicate severe heart problem 
• 
A sudden and temporary loss of consciousness (syncope) 
• 
Changes in the electrical activity of your heart that might lead to a heart rhythm problem and/or 
irregular heartbeat 
 
Uncommon (may affect less than 1 in 100 people) 
• 
Inflammation of the pancreas causing pain in the upper abdomen. This could become severe and 
may cause nausea and vomiting, fever and rapid heart rate. This could require hospitalization and 
may be life threatening 
• 
Suicidal thoughts  
• 
Psychosis 
 
Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised 
when driving or operating machines as patients may experience CNS effects.  
 
Possible Risks to Unborn Child 
 
Patients who agree to participate in this study should not become pregnant while on this study. Lorlatinib 
may cause fetal harm when administered to a pregnant woman and is not recommended during 
pregnancy or for women of childbearing potential not using contraception. Women of childbearing 
potential should use nonhormonal methods of birth control. If a hormonal method of birth control is 
unavoidable, then a condom must be used in combination with the hormonal method. Female patients 
must continue to follow these birth control guidelines for 21 days after finishing the study. Male patients 
must wear condoms as one of their forms of birth control for the duration of the study and for 97 days 
after finishing the study. Further contraception use should be discussed with your personal physician. If 
you or your partner becomes pregnant while you are participating in this study, please notify your doctor 
immediately.  For more information about risks and side effects, ask your doctor. 
 
Possible Long Term Side Effects of Treatment with Lorlatinib 
Side effects in adults treated with lorlatinib have occurred while patients have been receiving the drug or 
shortly after finishing the drug.  It is not known if some side effects may be seen only after a long time after 
finishing treatment with lorlatinib.   
 
Possible Risks from Having Blood Drawn 
The risks from having your blood taken are minimal, but can include an infection or a blood clot. Experienced 
doctors or nurses will perform these blood draws to minimize this risk.   
 
 
 

Unknown Risks 
The treatment may have side effects that no one knows about yet.  The researchers will let you know if they 
learn anything that might make you change your mind about participating in the study. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
There may or may not be direct medical benefit to you. The information learned from this study may or may 
not benefit other children or young people with solid cancers in the future. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
There are other options for you instead of this treatment. Instead of being in this study, you have these 
options: 
• 
Treatment with other chemotherapy medicines  
• 
Treatment with other experimental agents that may be available 
• 
No neuroblastoma therapy at this time, with care to help you feel more comfortable 
Please talk about these options with your doctor. 
 
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. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance and data 
analysis include: 
• 
New Approaches to Neuroblastoma Therapy (NANT) Consortium at Children’s Hospital Los 
Angeles in Los Angeles, CA.  The NANT Consortium identifies you by a number. 
• 
Independent auditor evaluating quality assurance for the NANT Consortium. 
• 
The National Cancer Institute (NCI) and other governmental agencies, like the Food and Drug 
Administration (FDA), Health Canada, or European regulatory agency(ies) involved in keeping 
research safe for people. 
• 
Foundation Medicine, Inc. who is a collaborator on this study.  
• 
Pfizer Inc., the pharmaceutical company which makes lorlatinib. 
 
NANT has received a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects. Information about the certificate is included at the end 
of this consent. 
 
Because this study involves the treatment of a medical condition, a copy of this consent form will be placed 
in your medical record. This will allow the doctors that are caring for you to obtain information about what 
medications or procedures you are receiving in the study and treat you appropriately. 
 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
Taking part in this study may lead to added costs to your insurance company.  Your health insurance 
company will be billed for many expenses associated with the costs of this study.  These expenses include 
medications, treatments, hospital charges, and doctors’ fees related to your participation in this study.   
 
Lorlatinib and the flavoring agent (Ora-Plus®) are being provided free of charge for use in this study, but 
the costs associated with administering the drug is normally covered by your insurance company.  The cost 
of doing a heart test called an EKG and neuropsychological testing at several time points during your 
participation in the study with lorlatinib is being done as part of research and will be paid for by the study.  
The special research blood and tissue studies will be done at no cost to you.  However, you or your health 
plan may need to pay for the costs of the supplies and personnel who draw the blood from you for these 
tests. 
  

You may have to pay for other things during this study, such as but not limited to, your time, the cost of 
food you buy while you are being treated at the hospital, car fare, travel to and from the hospital for 
treatment, parking, and baby sitter fees. 
Taking part in this study may lead to added costs that may not be covered by your insurance company. 
Please ask about any expected added costs or insurance problems. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
website at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .   You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this website. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)] if you feel that 
you have been injured because of taking part in this study. You can tell the doctor in person or call him/her 
at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study. You and/or your 
health plan will be charged for this treatment.  The study will not pay for medical treatment.  
 
WHAT ARE MY RIGHTS AS A STUDY PARTICIPANT? 
Taking part in this study is your choice. You may choose not to take part or not take part in the study. If you 
decide to take part in this study, you may remove yourself from 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. If you 
remove yourself from the study, we will still take care of you. We will explain what stopping the treatment 
may do and we will offer other treatments if they are available.  
 
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 case of injury resulting from this study, you do not lose any of you legal rights to seek payment by signing 
this form. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing data from this 
research throughout the study.  We will tell you about new information from this Board or other studies that 
may affect your health or willingness to stay in the study. 
 
 
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).  
 
WHO IS FUNDING THIS RESEARCH STUDY? 
This study is supported by Pfizer, Inc. Pfizer is a drug company that makes the drug being studied in this 
research project. Pfizer is giving money to Children's Hospital for some of the costs of the study. The results 
of the study will be reported to Pfizer. If the study shows that lorlatinib may be useful for a new purpose, 
this could benefit Pfizer financially. 
 
 

The Children’s Hospital Los Angeles/NANT is also providing funding for this study. 
 
Dr. Mossé at Children’s Hospital of Philadelphia, one of the principal investigators of this study, has served 
as a paid consultant to Pfizer. Her participation in this research has been reviewed and approved, subject 
to management, according to CHOP’s/NANT Conflict of Interest Policy.  
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the NCI’s Cancer Information Service at 
 
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615 
 
You may visit the NCI Web sites 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/ 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  
This website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this website at any time. 
 
You will get a copy of this consent form. If you want more information about this study, ask your doctor. 
 
 

CONSENT FOR EXTRA STUDIES FOR RESEARCH  
 
The following tests are optional for all patients in the study. You may still participate in the study 
even if you do not agree to these tests. 
 
1. Using extra blood to look for genetic changes seen in tumor cells 
 
Initial next to YES if you agree to let researchers take almost 4 extra teaspoons (17mL) at study entry 
and each time a disease evaluation is done)  to look at what genetic changes in your tumor can be seen 
in your blood over time before and after treatment with lorlatinib.  This blood would be drawn at a time 
when blood was being drawn for clinical purposes.  The blood will be sent to Foundation Medicine Inc. 
for analysis who is a collaborator on the study. The results of these tests will be confidential and not 
made available to you or your treating physician. 
 
Initial next to NO, if you do not want researchers to take extra blood above what is needed for clinical 
purposes. 
 
_______Yes       
_______No    
 
2. Comparing genetic changes between tumor leftover from a surgical procedure prior to relapse 
(diagnosis or second look) to relapsed neuroblastoma tumor tissue and bone marrow aspirates 
and whether these changes affect how the tumor will respond to treatment with lorlatinib. 
 
Initial next to YES, if you agree (and if there is tumor remaining)  to let this tumor be sent to a laboratory 
so researchers can compare these samples and determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  The results of 
these tests will be confidential and not made available to you or your treating doctor. 
 
Initial next to NO if you do not want leftover tumor from an earlier procedure to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely to 
respond to the drug lorlatinib. 
 
_______Yes      _______No   
 
 
Initial next to YES, if you agree to let extra bone marrow aspirates be collected to be sent to a laboratory 
so researchers can compare these samples and determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  The results of 
these tests will be confidential and not made available to you or your treating doctor. 
 
Initial next to NO if you do not want these bone marrow aspirates collected to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely to 
respond to the drug lorlatinib. 
 
_______Yes      _______No   
 

STATEMENT OF CONSENT 
 
I have already read the information in this informed consent document. I have read all the attachments that 
were included with this informed consent document. I have asked all of my questions and I have gotten 
answers. I agree to enroll myself (my child) in this study. 
 
 
_____________________________________ 
Print Patient Name 
 
 
______________________________________  
 
_____/_____/_____ 
Print Name of Parent or Guardian  
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Parent or Guardian  
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Patient (If > 7 years old) 
 
 
 
 
Date 
 
 
___________________________________________ 
 
_____/_____/______ 
Signature of Physician or  
 
 
 
 
 
Date 
Responsible Investigator 
 
_______________________________________ 
 
____/_____/______ 
Signature of Witness 
 
 
 
 
 
 
Date 
 
 
_______________________________________ 
 
____/_____/______ 
Signature of Translator  
 
 
 
 
 
Date 
 
 

Consent Addendum I: Tests That Will Be Done On This Study 
Observation 
Before Entry 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of 
Therapy 
Physical exam including 
neurological exam 
X 
Weekly 
Start of cycle 
Start of each cycle 
X 
Routine Blood tests** 
(Blood counts, 
electrolytes, liver, kidney 
function, function of 
pancreas- amylase/lipase) 
X 
Weekly 
Weekly for blood counts and 
twice during cycle for all 
other blood tests   
Start of each cycle 
X 
Routine Blood tests** 
(Fasting cholesterol, 
triglycerides, glucose) 
X 
Every other 
week  
Start of cycle  
Start of each cycle  
X 
Hemoglobin A1c (HbA1c)  
X  
 
Start of cycle  
With Disease 
Evaluations in 
Courses 4 and 6 
and after every 4 
courses thereafter  
X 
Pregnancy test 
(All females 10 years of 
age and older) 
X 
 
Start of cycle 
Start of each cycle 
 
Heart rhythm test 
(EKG)  
X 
One hour after 
day 1 treatment 
is finished 
End of cycle 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
Neuropsychological 
Testing  
Within one 
week before 
starting 
treatment 
End of cycle 
End of cycle 
 End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
Neuropsychological 
evaluation with licensed 
psychologist for patients 
less than 3 years of age 
Within one 
week before 
and up to two 
weeks after 
starting 
treatment 
 
End of cycle 
End of cycle 6, 10 
and then every 8 
cycles thereafter  
X 
Submit Patient Treatment 
Diaries 
 
X 
X 
X 
X 
Blood for Lorlatinib drug 
level tests (PK - Required) 
 
Day 1: 3 times 
Day 2: 1 time 
Day 15: 5 times 
 
 
 
Blood for circulating tumor 
cells (Optional) 
X 
 
With disease evaluation 
End of cycle (4,6, 
and every 4th cycle 
thereafter) 
 
Bone Marrow Aspirate 
(Optional) 
X 
 
With disease evaluation 
End of cycle (4,6, 
and every 4th cycle 
thereafter) 
 
Sampling of  leftover 
tumor tissue (Optional) 
Leftover tumor tissue can be sent at any time during the study 

 
Tests done during Disease Evaluation  
Bone marrow aspirate and 
biopsy 
X 
 
Week 4 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
CT/MRI scans and/or 
MIBG/PET scans 
Blood and bone marrow 
for NANT Biology study# 
# Patients enrolled in the companion biology study may have additional samples of blood and bone marrow collected at study entry 
and with each disease evaluation time point. Please look at the biology study N04-05 consent form for more information 
**Blood draws can be done more often if needed at the discretion of your study doctor 
 
 

Consent Addendum II 
Certificate of Confidentiality Information 
 
NANT 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. 
 
 
 
 
 
 
 
 
 

APPENDIX VII: LORLATINIB IN COMBINATION WITH CONVENTIONAL CHEMOTHERAPY (COHORT 
B2) SAMPLE CONSENT 
 
NANT 2015-02:  PHASE 1 STUDY OF LORLATINIB, AN ORAL SMALL MOLECULE INHIBITOR OF 
ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY NEUROBLASTOMA 
 
LORLATINIB IN COMBINATION WITH CONVENTIONAL CHEMOTHERAPY (COHORT B2): FOR 
PATIENTS ONE YEAR OF AGE THROUGH 30 YEARS OF AGE 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol. 
 
The word “you” used throughout this document refers to you or your child. 
 
WHAT IS THIS STUDY ABOUT? 
This study is a clinical trial, a type of research study. Clinical trials include only patients who choose to take 
part. Please take your time to make your decision about participating. You may discuss your decision with 
your friends, family, and health care team. If you have any questions, you may ask your doctor. 
 
You are being asked to participate in this study because you have a kind of cancer called neuroblastoma. 
It may be that your cancer went away for a while but has grown back (relapsed) or it may be that it has 
never gone away (persistent or resistant tumor) after standard treatment. Standard treatment may have 
included chemotherapy, surgery, radiation therapy, high-dose chemotherapy with a stem cell transplant 
and/or immunotherapy. 
 
WHY IS THIS STUDY BEING DONE? 
 
The purposes of this study are: 
 
• 
To find the highest safe dose of lorlatinib that can be given to children, adolescents and adults with 
refractory or relapsed neuroblastoma without causing severe side effects. 
 
• 
To learn about the side effects of the drug lorlatinib when given in combination with 
cyclophosphamide and topotecan) in children, adolescents and adults. 
 
• 
To determine if your tumor gets smaller after treatment with lorlatinib when given in combination 
with cyclophosphamide and topotecan. 
 
• 
To measure the levels of lorlatinib in the blood when given together with cyclophosphamide and 
topotecan in children and adolescents. 
 
• 
To look at genetic changes in tumor DNA found in the blood during treatment. 
 
• 
To look at genetic changes in tumor tissue to see if they affect response to lorlatinib. 
 
• 
To describe the amount of neuroblastoma tumor found in the blood and bone marrow by testing 
samples with a new test (called NB5 assay). 
 
The research is being done because: 
Currently there is no known effective treatment for your type of cancer. We are testing new experimental 
drugs such as lorlatinib in the hopes of finding a drug that may be effective against neuroblastoma tumors 
that have come back (relapsed) or that have never gone away (persistent/refractory) after treatment with 
standard therapy. This part of the study will combine three drugs: lorlatinib, cyclophosphamide and 
topotecan.  You may have taken cyclophosphamide and/or topotecan before (but not all three together) for 
treatment of your neuroblastoma. 

 
This study involves the use of an experimental drug called lorlatinib.  In laboratory testing, lorlatinib blocks the 
Anaplastic Lymphoma Kinase (ALK). ALK may be important in the growth of certain types of cancer cells 
such as neuroblastoma. Lorlatinib is considered experimental because it has not been proven to work in a 
situation like yours.  Lorlatinib has been approved by the United States Food and Drug Administration (FDA) 
to treat adults with non-small cell lung cancer, a different cancer than yours. It is not approved for 
neuroblastoma.  Lorlatinib has been used only in a small number of adults so there is a lot we do not know 
about it yet.  Lorlatinib has not previously been used in children and adolescents not enrolled on this study. 
 
Cyclophosphamide and topotecan are chemotherapy drugs that are FDA-approved for the treatment of 
certain adult cancers, but have not been approved to treat children with neuroblastoma. These drugs have 
been used in combination to treat many children with neuroblastoma and in some patients this combination 
has reduced the amount of neuroblastoma present. Even if you have previously received treatment with 
cyclophosphamide and topotecan, you can still participate in this study. 
 
All patients enrolled on this study are known to have a defect in the ALK gene in their tumor before they 
start treatment. You or your doctor should have the results of this test before being able to enroll on this 
study.  
 
A dose of lorlatinib that can be given safely to children and adolescents was chosenfrom the dose escalation 
part of the study.  Lorlatinib has not been given in combination with chemotherapy in patients with childhood 
tumors. In this part of the study, we will test the dose of lorlatinib that can be given safely in combination 
with cyclophosphamide and topotecan to children, adolescents and adults up to age 30 with 
relapsed/refractory neuroblastoma. After 4 cycles of chemotherapy, you and your physician may decide to 
stop the chemotherapy and continue lorlatinib without the chemotherapy.   
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
There will be about 60-75 patients enrolling on the 4 study cohorts.  Of this number, about 12-18 children 
and adolescents and adults up to age 30 will be enrolled on this part of the study where lorlatinib is given 
together with cyclophosphamide and topotecan). 
 
WHAT WILL HAPPEN TO ME IF I TAKE PART IN THIS STUDY? 
 
Before You Begin the Study  
Your doctor will have previously sent your tumor for genetic testing and these results showed your tumor 
has a defect in the ALK gene which allows you to be considered for participation in this study (Cohort B2). 
 
You will need to have the following exams, tests or procedures to find out if you can take part in the study. 
Most of these exams, tests or procedures are part of regular cancer care and may be done even if you do 
not join the study.   
These tests will also be done at various times throughout the study and at the end of the study.  The purpose 
of these tests is to see how well the treatment works and to measure the status of your neuroblastoma.   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 
Bone marrow tests3 to check your tumor 
Blood tests1 
Various scans4 to check your tumor 
Pregnancy test (urine or blood)2 
Electrocardiogram (EKG) to check the heart rhythm5 
 
Neuropsychological testing6 
1Some blood tests (cholesterol and fat digestion [triglycerides]) may need to be done on an empty stomach, 
so you cannot eat or drink anything other than water for 8 hours before these tests are done (called fasting).  
Your doctor or nurse will tell you if it is necessary for you to fast before these blood tests are done. 
 

2If you are a female at least 10 years old or who could have children, you will have a pregnancy test done 
by the doctor the week before starting treatment and then before each cycle of treatment begins. Both you 
and your parent/legal guardian (if applicable) will be informed of a positive pregnancy test. All men and 
women who could have children must either agree to practice abstinence from heterosexual intercourse or 
use two effective methods of birth control for as long as they participate in this study.  
 
3Bone marrow tests are done by inserting a needle into the hip bone to remove the marrow which is inside 
the bone. 
 
4Various scans are done for diagnosis and checking the response of the tumor to treatment. These may 
include CT and /or MRI scans and MIBG or PET scans. We will recommend scans specific for your case 
and we will answer your questions about these scans. 
 
5Electrocardiogram (EKG) to document your heart rhythm before beginning lorlatinib treatment.  
 
6Central nervous system effects (speech, memory and mood changes) were seen in previous studies 
treating adults with Lorlatinib.  Neuropsychological testing will be done at within one week of starting 
treatment and at different times during this study to monitor for any changes in thinking skills, behavior and 
mood.   Please see the section on Neuropsychological testing below in “During the Study” for more details 
on what tests are done and when they are done during this study. 
 
During the Study   
If the exams, tests and procedures show that you can be in the study, and you choose to take part, lorlatinib 
will be given once a day for 28 days and will be given together with cyclophosphamide/topotecan on the 
first 5 days.  This entire period is called a cycle with each treatment cycle being 28 days long.  You may 
continue to receive treatment with lorlatinib and cyclophosphamide/topotecan for up to 24 cycles or 
indefinitely if you are no longer receiving chemotherapy unless you develop serious side effects or your 
tumor worsens. 
 
One Treatment Cycle  
Cohort B2:  Lorlatinib with chemotherapy 
Week 1 
Week 2 
Week 3 
Week 4 
 Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Days  
8-14 
Days  
15 -21 
Days 22-28 
 
*Lorlatinib  once a day 
 
CPM 
CPM 
CPM 
CPM 
CPM 
 
 
 
 
 
TOPO 
TOPO 
TOPO 
TOPO 
TOPO 
MGF 
 
 
 
 
 
CPM: Cyclophosphamide 
 
TOPO: Topotecan 
 
MGF:  Myeloid growth factor 
*Lorlatinib should be given at least one hour before chemotherapy on days 1-5 of each cycle.  
 
Lorlatinib 
Lorlatinib will be given by mouth once a day followed by a small glass of water. Lorlatinib should be given 
at least one hour before chemotherapy on days 1 – 5 of each cycle.   If you vomit lorlatinib within 20 minutes 
of taking the dose for the day, that dose can be repeated.  This is the only time a dose of lorlatinib can be 
repeated.  
 
 

Lorlatinib will be available as a tablet. If you are unable to swallow the tablets whole, you will be instructed 
on how to make a liquid lorlatinib solution at home by mixing the lorlatinib tablets with water and a flavoring 
agent (Ora-Plus®). Your nurse or doctor will help you decide what is best for you and will make sure you 
have the proper directions for taking this medication. 
 
You will be given a patient diary at the beginning of each cycle of lorlatinib.  Use the diary to record the date 
and time you take the drug, all vomited and missed doses, side effects that you experience and any other 
medications and supplements you are taking.  The diary should be returned to clinic along with the 
medication bottle (even if it is empty) weekly during cycle 1 and then at the end of each treatment cycle.  
This will help us to know how much of the drug you take and how it made you feel. 
 
Cyclophosphamide & Topotecan 
You will receive both cyclophosphamide and topotecan into the bloodstream (either through your central 
line or through a small tube placed in a vein in your hand or arm) on days 1 through 5 of each cycle.  You 
will receive each medicine over 30 minutes and the cyclophosphamide will be given first.  These medicines 
are typically given in the clinic. You may stop cyclophosphamide and topotecan after 4 courses after 
discussion with your physician if it is deemed to be in your interest.    
 
Myeloid Growth Factor 
In addition, you will be given a medicine to help boost your white blood cell count.  White blood cells help 
fight infection and having low white blood cells can increase your risk of developing an infection. This drug 
will be started on day 6 of each treatment cycle if you receive chemotherapy.  Filgrastim or G-CSF is a shot 
given into the skin each day until the white blood cell count increases.  Pegfilgrastim is a long-acting version 
of Filgrastim that is given as shot into the skin just once on day 6 of the cycle.  Your doctor will talk with you 
about which of these study drugs you will receive.  
 
During the study you will have tests and procedures done to check for side effects from taking lorlatinib in 
combination with chemotherapy and to see how your tumor is doing.  Many of these tests are part of regular 
cancer care but you may have them done more often because you are on the study: 
 
Physical exam 
Electrocardiogram (EKG) to test heart rhythm 3 
Blood tests 1 
Bone marrow tests & various scans (CT/MRI, MIBG or PET) to check 
your tumor 4 
Pregnancy test (urine or 
blood) 2 
Neuropsychological testing 5 
 
1 Some blood tests (cholesterol and fat digestion) may be done on an empty stomach, so patients cannot 
eat or drink anything other than water for 8-10 hours before these tests are done.   
 
2 A urine or blood pregnancy test will be done before each treatment cycle begins if you are a female at 
least 10 years old or who could have children.  Both you and your parent/legal guardian will be informed of 
a positive pregnancy test. All men and women who could have children must continue to practice 
abstinence from heterosexual intercourse or use two effective methods of birth control for as long as they 
participate in this study.  
3 Electrocardiogram (EKG) done before starting study treatment will be repeated at certain times during the 
study to document if lorlatinib treatment has any effect on heart rhythm. 
 
4 Bone marrow tests and various scans are done for checking the response of your tumor to treatment.  
These tests will be done at certain times during the study to look at response to lorlatinib and check that 
your tumor has not gotten worse. 
 
 
 

5Neuropsychological Testing 
Neuropsychological evaluations try to understand how changes in the health of the brain may affect 
behavior or mood and how well a person is able to pay attention, remember things or solve problems.  Since 
effects on speech, memory and mood were seen in a small number of adults receiving lorlatinib, 
neuropsychological testing will be done to monitor for changes in thinking skills, behavior and mood at 
different times during this study. Testing methods are based on the age of the patient and include 
computerized tests using an iPad, written questionnaires and evaluations by a licensed psychologist.  
Parents or legal guardians of patients less than 18 years of age will also participate by completing written 
questionnaires at the same time their child is being tested.   
 
The results of the neuropsychological testing will be told to your doctor and entered as part of your medical 
record. Neuropsychological results will be used to make decisions about your care while enrolled on this 
study.  If the testing results show areas of concern, you may be given more frequent testing as well as 
referrals for other care if needed.  During testing, patients may skip questions that are stressful and may 
stop taking the tests at any time.  Testing can be done as part of the clinic visit.  You will need to talk with 
your doctor and nurse about scheduling to do these tests at times that are workable for you and your child.  
Please see the table at the end of the consent form that tells how often these tests will be done during the 
study. 
 
• 
All patients 3 years of age and older will do computerized tests using an iPad.  While the patient is 
taking these tests, the patient’s parent or legal guardian will complete written questionnaires about 
the patient’s mood and emotions, behavior, daily living/functional skills and social skills with others.  
The parent/legal guardian can be in the same room during the testing but they cannot help their 
child with their tests.   
 
• 
Patients 18 years of age will complete computerized tests using an iPad and their own written 
questionnaires.  Parents/Legal guardians do not have testing to do with patients of this age. 
 
• 
Patients under 3 years of age will have an evaluation of overall functioning including language, 
motor and cognitive development done by a licensed psychologist.  Parents/legal guardians will 
also complete written questionnaires at the same time. 
 
Patient age at 
testing in years 
Testing being done 
Length of testing time  
for Patients 
Length of testing time for 
Parents/legal guardians 
1 
Patient: licensed psychologist 
Parent/legal guardian: written 
questionnaires 
~ 60 - 90 minutes 
~ 20 minutes 
2 
~ 50 minutes 
3 - 5 
Patient: computerized tests using  an 
iPad 
Parent/legal guardian: written 
questionnaires 
~ 10 minutes 
~ 50 minutes 
6 
~ 30 – 40 minutes 
~ 50 minutes 
7 - 9 
~ 30 – 40 minutes 
~ 50 - 55 minutes 
10 - 17 
~ 35 – 45 minutes 
~ 50 - 55 minutes 
18 
Patient: computerized tests using an 
iPad and written questionnaires 
~ 80 – 90 minutes 
NA 
 
 
NANT Biology Study (NANT 2004-05) 
If you choose to participate in this research, you will also be asked to join a companion NANT biology study 
to collect blood, bone marrow and tumor tissue (if available) and reports from radiology scans from patients 
with neuroblastoma. The biology study also provides a place (called NANT biorepository) where any leftover 
samples of tumor tissue or bone marrow and blood collected on this study could be transferred and stored. 
While you will be asked to join the Biology Study (NANT 2004-05), the decision to store/bank any leftover 

samples is optional and will not affect your ability to participate in this treatment study with lorlatinib.  Your 
doctor will talk with you in detail about the NANT biology study and have you sign a separate consent form. 
 
Additional Tests in this Study 
We would like to do some extra tests called pharmacokinetic studies and biologic studies.  These tests will 
help us learn more about lorlatinib and may help children and adolescents 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 meaning you can decide whether you 
want to do them or not.  
 
Pharmacokinetic Studies: Determining Blood Levels of Lorlatinib – Required  
During this study blood samples will be collected to determine how much lorlatinib is in your blood (called 
pharmacokinetics). About 3mL (just over half a teaspoon) of blood will be drawn with each sample.  A total of 
9 blood samples will be obtained over 3 separate days during course 1 (Day 1, Day 2 and Day 15).  The total 
amount of blood drawn for testing will be about 27 mL (almost 5 ½ teaspoons). If you have a central line (such 
as a port or a Broviac) these samples can be drawn through that line or through a small tube placed in a vein 
in your hand or arm.  This amount of blood is considered safe to donate. Samples will be sent to a commercial 
laboratory contracted to perform these tests for the study. These samples will be the property of Pfizer and 
Pfizer may also use the PK Biological Samples for evaluation of the bioanalytical method. 
 
Other Biology Research Tests in this Study - Optional 
You will be asked if you want to participate in 3 optional research tests.  You can decide not to let the doctors 
do these tests and still be able to be treated as part of this study.  There are checkboxes at end of this form 
to mark whether you are willing to participate in these voluntary studies. The results of these research tests 
will not be shared with you or become part of your medical record.  These results would also not be used to 
make decisions about your care while enrolled on this study.    
 
• 
Using extra blood to look for genetic changes seen in tumor cells. 
Tumor cells often release small pieces of DNA into the blood stream where it can be detected by 
sensitive tests.  About 17mL (almost four teaspoons) of blood will be drawn at study entry and at 
each time disease evaluation testing is done (after cycles 2, 4, 6 and then every 4th cycle) to look at 
what genetic changes in your tumor may be seen over time from the small pieces of tumor DNA 
found in your blood. The blood will be sent to a commercial laboratory contracted to perform this 
testing for the study.  
 
• 
Comparing genetic changes between leftover tumor from a surgical procedure prior to tumor 
relapse (at diagnosis or when you had surgery done after diagnosis) to relapsed 
neuroblastoma tumor tissue and bone marrow aspirates and whether these changes affect 
how the tumor will respond to treatment with Lorlatinib. 
 Researchers would like to look at tumor tissue to determine if there are certain gene changes  
 present that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.   
 These tests would be done on tumor tissue remaining from diagnosis, or any previous surgery  
 where tumor tissue was removed (removal of primary tumor or removal of tumor at a relapse) in  
 the past. The tissue and bone marrow aspirates will be sent to a research laboratory at Children’s   
 Hospital of Philadelphia for testing.     
 
When You Have Finished Treatment with Lorlatinib  
After you stop treatment on this study, you will continue to have tests and scans done (listed below) to 
measure how much tumor is left. If test results show you have abnormal organ functions, tests are 
recommended by the study to be repeated monthly until test results are stable or normal. You doctor will 
tell you how often these tests and evaluations will be done. 
 
 

Medical Tests after the Study: 
 
Physical exam  
Neuropsychological testing1 
Blood tests 
Bone marrow tests & various scans (CT/MRI, MIBG or PET) 
to check your tumor2 
Electrocardiogram (EKG) to 
check the heart rhythm3 
 
 
1The same neuropsychological testing and evaluation done before starting study treatment will be done at 
the end of treatment with lorlatinib.  The need for any further testing after this will be up to your doctor. 
 
2Bone marrow tests and various scans are done for checking the response of your tumor to treatment.  
These tests will be done at the end of a course and at certain times following treatment to monitor your 
tumor status. 
 
3Electrocardiogram (EKG) done at the end of the study to document if lorlatinib treatment has any effect on 
heart rhythm.  
 
A table detailing the tests and procedures required before, during and after the study has been attached to 
the end of this form (Consent Addendum 1). 
 
HOW LONG WILL I BE ON THIS STUDY?  
You can get up to 24 cycles with lorlatinib and chemotherapy or indefinitely if you are no longer receiving 
chemotherapy as long as you are not having bad side effects and as long as your tumor is not getting 
worse.   
 
After you stop treatment, you will continue to have tests and scans done to measure how much tumor is left. 
Your doctor will tell you how often these tests will be done. Researchers will continue to collect information 
about you for a lifetime. Information will be collected about whether you are still alive; whether your tumor has 
grown back and at what sites in the body; whether you have developed any side effects from the treatment; 
or whether you have developed any additional cancer. Your oncologist or family doctor will give the 
researchers this information at regular intervals. 
 
CAN I STOP BEING IN THE STUDY? 
Yes. If you are thinking about stopping your participation on this study, you should talk to your doctor before 
making a final decision so he/she can tell you how to do this safely.  
 
Your doctor may also stop you from taking part in this study at any time if he/she believes it is in your best 
interest; if you do not follow study rules; or if the study is stopped. 
 
WHAT ARE THE RISKS OF THE STUDY? 
This is a Phase 1 study.  A Phase 1 study looks at how common and serious side effects can be for each 
patient at a specific dose of a drug. In a Phase 1 study, some patients may have very serious side effects 
and could die as a result of these side effects. You may be one of those patients who have serious side 
effects as a result of participating in this Phase 1 study.  
 
In this study, researchers will be looking at side effects seen in patients taking different doses of lorlatinib 
as well as lorlatinib given together with chemotherapy.  
Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know 
all the side effects that may happen. Side effects may be mild or very serious. Other drugs may be given 
to make side effects less serious and more comfortable.   Many side effects go away soon after you stop 
taking the study medications but it is always possible that side effects can be serious, long lasting or may 
never go away. There is also a risk of death. Patients are watched carefully and treatment will be stopped 

if bad side effects develop. There may also be risks we do not know about. You should talk to your doctor 
about any side effects that you have while taking part in this study.  
 
While on the study, you are at risk for the side effects listed below: 
 
Possible Risks of Lorlatinib: 
 
The following side effects are considered to be related to lorlatinib have been reported:  
Very Common  
(may affect 10 or more in 100 people) 
Common 
(may affect from 1 up to less than 10 in 100 people) 
• 
Increase in cholesterol and triglycerides 
(fats in your blood)  
• 
Effects on mood (for example, irritability 
and mood swings)  
• 
Effects on memory (for example, 
confusion, memory loss and disturbance 
of attention)  
• 
Effects on the peripheral nerves which are 
those outside of the brain and spinal cord, 
including tingling, numbness or pain in 
hands and feet)  
• 
Changes in vision (including double 
vision, perceived flashes or floaters of 
light, light intolerance, vision blurred, 
vision sharpness reduced and visual 
impairment) 
• 
Hypertension  
• 
Diarrhea  
• 
Constipation  
• 
Joint pain  
• 
Build-up of fluid in the body or extremities 
causing swelling (edema)  
• 
Fatigue (feeling tired and exhausted)  
• 
Increase in body weight 
• 
Increase in blood sugar levels 
• 
Hallucination and loss of contact with 
reality 
• 
Changes in mental status  
• 
Changes in speech (for example, slow 
speech or slurred speech) 
• 
Inflammation of the lungs (pneumonitis) 
which can cause shortness of breath and 
difficulty breathing. If severe, this can be 
life threatening.  
 
 
 
 
 
 
 
 
 

The following events have also been reported in patients while they were taking lorlatinib, although the 
relationship to lorlatinib is uncertain:  
 
Very common (may affect 10 or more in 100 people) 
• 
Abnormalities in blood tests that may indicate liver damage 
• 
Abnormal pancreas tests 
• 
Decrease in hemoglobin in the blood that can cause weakness 
• 
Headache 
• 
Muscle pain 
• 
Difficulty sleeping 
• 
Rash 
 
Common (may affect from 1 up to less than 10 in 100 people) 
• 
Decrease of ejection fraction of the heart which may indicate severe heart problem 
• 
A sudden and temporary loss of consciousness (syncope) 
• 
Changes in the electrical activity of your heart that might lead to a heart rhythm problem and/or 
irregular heartbeat 
 
Uncommon (may affect less than 1 in 100 people) 
• 
Inflammation of the pancreas causing pain in the upper abdomen. This could become severe and 
may cause nausea and vomiting, fever and rapid heart rate. This could require hospitalization and 
may be life threatening 
• 
Suicidal thoughts  
• 
Psychosis 
 
Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised 
when driving or operating machines as patients may experience CNS effects.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Possible Side Effects of Cyclophosphamide: 
 
Likely 
Less Likely 
Rare But Serious 
• 
Loss of appetite 
• 
Nausea  
• 
Vomiting 
• 
Fewer white blood cells in the 
blood. 
○ 
A low number of white blood 
cells may make it easier to 
get infections. 
• 
Hair loss 
• 
Decreased ability of the body to 
fight infection  
• 
Absence  or decrease in the 
number of  sperm  which may be 
temporary or permanent which 
may decrease the ability to have 
children 
 
 
• 
Abdominal pain 
• 
Diarrhea 
• 
Fewer red blood cells and 
platelets in the blood 
○ 
A low number of red blood 
cells may make you feel 
tired and weak. 
○ 
A low number of platelets 
may cause you to bruise 
and bleed more easily. 
• 
Bleeding and inflammation of 
the urinary bladder 
• 
Absence  or decrease monthly 
periods which may be 
temporary or permanent and 
which may decrease the ability 
to have children 
 
• 
Temporary blurred vision 
• 
Nasal stuffiness with fast IV 
infusions 
• 
Irregular heart rate with fast IV 
infusions 
• 
Skin rash 
• 
Severe allergic reaction which 
can be life threatening with 
shortness of breath, low blood 
pressure, rapid heart rate 
chills and fever 
• 
Abnormal hormone function 
which may lower the level of 
salt in the blood  
• 
Heart muscle damage which 
may occur with very high 
doses and which may be fatal 
• 
Darkening of areas of the skin 
and finger nails 
• 
Fingernail changes 
• 
Slow healing of wounds 
• 
Infections  
• 
Infertility which is the inability to 
have children 
• 
Damage and scarring of lung 
tissue which may make you 
short of breath 
• 
A new cancer or leukemia 
resulting from this treatment. 
• 
Damage or scarring of urinary 
bladder tissue 
 

Possible Side Effects of Topotecan: 
 
Likely 
Less Likely 
Rare But Serious 
• 
Diarrhea  
• 
Nausea 
• 
Vomiting 
• 
Constipation 
• 
Fewer white blood cells, red 
blood cells and platelets in the 
blood. 
o 
A low number of white 
blood cells can make it 
easier to get infections 
o 
A low number of red blood 
cells can make you feel 
tired and weak 
o 
A low number of platelets 
causes you to bruise and 
bleed more easily 
• 
Fever including fever with a low 
white blood cell count which 
could indicate infection and 
may require hospitalization and 
treatment with antibiotics 
• 
Pain which may be in your 
abdomen, back or bones 
• 
A feeling of weakness and/or 
tiredness 
• 
Temporary hair loss 
• 
Loss of appetite 
• 
Headache 
• 
Lack of muscle strength 
or weakness 
• 
Rash, hives, itching or a 
red bumpy rash 
• 
A mild lowering of the 
blood pressure which 
usually does not require 
treatment 
• 
Shortness of breath 
• 
Inflammation and/or 
sores in the mouth, 
throat and/or esophagus 
• 
Elevation in the blood of 
certain enzymes found in 
the liver which may 
indicate liver irritation or 
damage 
• 
An infection in the blood 
which will require 
admission to the hospital 
and treatment with 
antibiotics 
 
• 
Severe allergic reaction which can be 
life threatening with shortness of 
breath, low blood pressure and a 
rapid heart rate 
• 
Severe allergic reaction which can be 
life threatening with rapid build-up of 
fluid under the skin, in the lining of the 
intestine and possibly in the throat or 
swelling of the tongue which could 
make it difficult to breath. 
• 
Chest pain 
• 
Shaking chills  
• 
Elevation in the blood of certain 
enzymes or bilirubin found in the liver 
which could indicate liver irritation or 
damage 
• 
Numbness and tingling in the fingers 
and toes 
• 
Muscle or joint aches and pains 
• 
Bleeding into the tumor which may 
cause damage depending on the 
location of the tumor 
• 
Small amount of blood and/or protein 
in the urine or an elevation in blood 
creatinine which may indicate mild 
kidney damage 
 
 
 
 
 

Growth Factors are not anti-cancer medicines.  It helps the growth of white blood cells that fight infection 
(filgrastim/pegfilgrastim).  
 
Possible Side Effects of Neupogen (Filgrastim): 
 
Likely  
(happens to 21-100 
children out every 
100 children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out every 100 children) 
• 
Aching or 
pain in 
bones. 
• 
Local irritation/pain at the site 
of the injection. 
• 
Higher than normal levels in 
the blood of uric acid and of 
liver enzymes which may 
indicate liver irritation or 
damage. 
• 
Fever 
• 
A low number of platelets in 
the blood which may cause 
you to bruise and bleed more 
easily. 
• 
Allergic reactions which can be life threatening 
with shortness of breath, low blood pressure, 
rapid heart rate, hives, facial swelling. This 
reaction is very rare and has been associated 
mainly with intravenous administration. 
• 
If you are known to have sickle cell disease , 
this drug may cause sickle cell crises  
• 
Severe damage to the spleen (an organ in the 
abdomen which stores blood cells) which could 
lead to pain and loss of blood into the abdomen 
or rupture of the spleen. 
• 
Difficulty breathing and lung damage that may 
be due to the white blood cells, stimulated by 
Pegfilgrastim , travelling to the lungs when they 
are inflamed or infected (Adult Respiratory 
Distress Syndrome)  
• 
Bone marrow dysfunction (MDS) or secondary 
leukemia in patients with very bad ongoing low 
white cell counts that require prolonged 
administration of this drug. 
• 
Worsening of skin rashes 
• 
Low Fever 
• 
Inflammation of blood vessels leading to a 
raised purple rash and bruising 
• 
Higher than normal white blood count. 
• 
Low blood pressure and/or increased heart rate 
• 
Wheezing or shortness of breath 
• 
Skin rash, hives or facial swelling 
 

Possible Side Effects of Neulasta (Pegfilgrastim): 
 
Likely  
(happens to 21-100 
children out every 100 
children) 
Less Likely 
(happens to 5-20 children out 
every 100 children) 
Rare 
(happens to < 5 children out every 100 children) 
 
• 
Aching or 
pain in 
bones. 
 
• 
Local irritation at the site of 
the injection. 
• 
Headache 
• 
Higher than normal levels in 
the blood of uric acid and of 
liver enzymes which may 
indicate liver irritation or 
damage. 
• 
A low number of platelets in 
the blood which may cause 
you to bruise and bleed 
more easily. 
 
 
 
 
 
 
• 
Low grade fever 
• 
Allergic reactions which can be life threatening 
with shortness of breath, low blood pressure, 
rapid heart rate, hives, facial swelling. This 
reaction is very rare and has been associated 
mainly with intravenous administration. 
• 
Redness and flushing of the face and body. 
• 
Enlarged spleen 
• 
Severe damage to the spleen (an organ in the 
abdomen which stores blood cells) which could 
lead to pain and loss of blood into the abdomen. 
• 
If you are known to have sickle cell disease , this 
drug may cause sickle cell crises  
• 
Markedly higher than normal white blood cell 
count which may be associated with fever and 
red, often painful patches on the skin (Sweet's 
syndrome). 
• 
Difficulty breathing and lung damage that may be 
due to the white blood cells, stimulated by 
Pegfilgrastim, travelling to the lungs when they 
are inflamed or infected (Adult Respiratory 
Distress Syndrome) 
  
Possible Risks to Unborn Child 
Patients who agree to participate in this study should not become pregnant while on this study. Lorlatinib 
may cause fetal harm when administered to a pregnant woman and is not recommended during 
pregnancy or for women of childbearing potential not using contraception. Women of childbearing 
potential should use nonhormonal methods of birth control. If a hormonal method of birth control is 
unavoidable, then a condom must be used in combination with the hormonal method. Female patients 
must continue to follow these birth control guidelines for 21 days after finishing the study. Male patients 
must wear condoms as one of their forms of birth control for the duration of the study and for 97 days 
after finishing the study. Further contraception use should be discussed with your personal physician. If 
you or your partner becomes pregnant while you are participating in this study, please notify your doctor 
immediately.  For more information about risks and side effects, ask your doctor. 
 
Possible Long Term Side Effects of This Treatment 
Side effects in adults treated with lorlatinib have occurred while patients have been receiving the drug or 
shortly after finishing the drug.  It is not known if some side effects may be seen only after a long time after 
finishing treatment with lorlatinib.   
 
Possible Risks from Having Blood Drawn 
The risks from having your blood taken are minimal, but can include an infection or a blood clot. Experienced 
doctors or nurses will perform these blood draws to minimize this risk.   
 
Unknown Risks 
The treatment may have side effects that no one knows about yet.  The researchers will let you know if they 
learn anything that might make you change your mind about participating in the study. 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
There may or may not be direct medical benefit to you. The information learned from this study may or may 
not benefit other children or young people with solid cancers in the future. 

 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
There are other options for you instead of this treatment. Instead of being in this study, you have these 
options: 
 
• 
Treatment with other chemotherapy medicines  
• 
Treatment with other experimental agents that may be available. 
• 
No neuroblastoma therapy at this time, with care to help you feel more comfortable. 
 
Please talk about these options with your doctor. 
 
 
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. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance and data 
analysis include: 
• 
New Approaches to Neuroblastoma Therapy (NANT) Consortium at Children’s Hospital Los 
Angeles in Los Angeles, CA.  The NANT Consortium identifies you by a number. 
• 
Independent auditor evaluating quality assurance for the NANT Consortium. 
• 
The National Cancer Institute (NCI) and other governmental agencies, like the Food and Drug 
Administration (FDA) or Health Canada, involved in keeping research safe for people. 
• 
Foundation Medicine, Inc. who is a collaborator on this study.  
• 
Pfizer Inc., the pharmaceutical company which makes lorlatinib. 
 
NANT has received a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects. Information about the certificate is included at the end 
of this consent. 
 
Because this study involves the treatment of a medical condition, a copy of this consent form will be placed 
in your medical record. This will allow the doctors that are caring for you to obtain information about what 
medications or procedures you are receiving in the study and treat you appropriately. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
Taking part in this study may lead to added costs to your insurance company.  Your health insurance 
company will be billed for many expenses associated with the costs of this study.  These expenses include 
medications, treatments, hospital charges, and doctors’ fees related to your participation in this study.   
 
Lorlatinib and the flavoring agent (Ora-Plus®) are being provided free of charge for use in this study, but 
the costs associated with administering the drug is normally covered by your insurance company. 
Cyclophosphamide and topotecan is normally covered by your insurance company. The cost of doing a 
heart test called an EKG and neuropsychological testing at several time points during your participation in 
the study with Lorlatinib is being done as part of research and will be paid for by the study.  
The special research blood and tissue studies will be done at no cost to you.  However, you or your health 
plan may need to pay for the costs of the supplies and personnel who draw the blood from you for these 
tests. 
  
You may have to pay for other things during this study, such as but not limited to, your time, the cost of 
food you buy while you are being treated at the hospital, car fare, travel to and from the hospital for 
treatment, parking, and baby sitter fees. 
 

Taking part in this study may lead to added costs that may not be covered by your insurance company. 
Please ask about any expected added costs or insurance problems. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .   You can print a copy of 
the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that 
you have been injured because of taking part in this study. You can tell the doctor in person or call him/her 
at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study. You and/or your 
health plan will be charged for this treatment.  The study will not pay for medical treatment.  
 
WHAT ARE MY RIGHTS AS A STUDY PARTICIPANT? 
Taking part in this study is your choice. You may choose not to take part or not take part in the study. If you 
decide to take part in this study, you may remove yourself from 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. If you 
remove yourself from the study, we will still take care of you. We will explain what stopping the treatment 
may do and we will offer other treatments if they are available.  
 
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 case of injury resulting from this study, you do not lose any of you legal rights to seek payment by signing 
this form. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing data from this 
research throughout the study.  We will tell you about new information from this Board or other studies that 
may affect your health or willingness to stay in the study. 
 
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).  
 
 
WHO IS FUNDING THIS RESEARCH STUDY? 
This study is supported by Pfizer, Inc. Pfizer is a drug company that makes the drug being studied in this 
research project. Pfizer is giving money to Children's Hospital for some of the costs of the study. The results 
of the study will be reported to Pfizer. If the study shows that lorlatinib may be useful for a new purpose, 
this could benefit Pfizer financially. 
 
 
 
 

The Children’s Hospital Los Angeles/NANT is also providing funding for this study. 
 
Dr. Mossé at Children’s Hospital of Philadelphia, one of the principal investigators of this study, has served 
as a paid consultant to Pfizer. Her participation in this research has been reviewed and approved, subject 
to management, according to CHOP’s/NANT Conflict of Interest Policy.  
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the NCI’s Cancer Information Service at 
 
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615 
 
You may visit the NCI Web sites 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/ 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  
This website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this website at any time. 
 
You will get a copy of this consent form. If you want more information about this study, ask your doctor. 
 
 
 
 
 
 

CONSENT FOR EXTRA STUDIES FOR RESEARCH  
 
The following tests are optional for all patients in the study. You may still participate in the study 
even if you do not agree to these tests. 
 
1. Using extra blood to look for genetic changes seen in tumor cells 
Initial next to YES if you agree to let researchers take almost 4 extra teaspoons (17mL) at study entry 
and each time a disease evaluation is done)  to look at what genetic changes in your tumor can be seen 
in your blood over time before and after treatment with lorlatinib.  This blood would be drawn at a time 
when blood was being drawn for clinical purposes.  The blood will be sent to Foundation Medicine Inc. 
for analysis who is a collaborator on this study. The results of these tests will be confidential and not 
made available to you or your treating physician. 
 
Initial next to NO, if you do not want researchers to take extra blood above what is needed for clinical 
purposes. 
 
_______Yes       
_______No    
 
 
2. Comparing genetic changes between tumor leftover from a surgical procedure prior to relapse 
(diagnosis or second look) to relapsed neuroblastoma tumor tissue and bone marrow aspirates 
and whether these changes affect how the tumor will respond to treatment with Lorlatinib. 
 
Initial next to YES, if you agree (and if there is tumor remaining)  to let this tumor be sent to a laboratory 
so researchers can compare these samples and determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  The results of 
these tests will be confidential and not made available to you or your treating doctor. 
 
Initial next to NO if you do not want leftover tumor from an earlier procedure to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely to 
respond to the drug lorlatinib. 
 
_______Yes      _______No   
 
 
Initial next to YES, if you agree to let extra bone marrow aspirates be collected to be sent to a laboratory 
so researchers can compare these samples and determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  The results of 
these tests will be confidential and not made available to you or your treating doctor. 
 
Initial next to NO if you do not want these bone marrow aspirates collected to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely to 
respond to the drug lorlatinib. 
 
_______Yes      _______No   
 
 
 
 
 
 
 

STATEMENT OF CONSENT 
 
I have already read the information in this informed consent document. I have read all the attachments that 
were included with this informed consent document. I have asked all of my questions and I have gotten 
answers. I agree to enroll myself (my child) in this study. 
 
 
_____________________________________ 
Patient Name 
 
 
______________________________________  
 
_____/_____/_____ 
Print Name of Parent or Guardian 
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Parent or Guardian  
 
 
 
 
Date 
 
 
______________________________________  
 
_____/_____/_____ 
Signature of Patient (If > 7 years old) 
 
 
 
 
Date 
 
 
___________________________________________ 
 
_____/_____/______ 
Signature of Physician or  
 
 
 
 
 
Date 
Responsible Investigator 
 
_______________________________________ 
 
____/_____/______ 
Signature of Witness 
 
 
 
 
 
 
Date 
 
 
_______________________________________ 
 
____/_____/______ 
Signature of Translator  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 

Consent Addendum I: Tests That Will Be Done On This Study 
Observation 
Before Entry 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of Therapy 
Physical exam 
including neurological 
exam 
X 
Weekly 
Start of cycle 
Start of each cycle 
X 
Routine blood tests** 
(Blood counts, 
electrolytes, liver, 
kidney function, 
function of pancreas-
amylase/lipase) 
X 
Weekly for other 
tests and twice 
weekly for blood 
counts 
Weekly for blood counts and twice 
during cycle for all other blood 
tests   
Start of each cycle 
and weekly for blood 
counts 
X 
Routine Blood tests** 
(Fasting cholesterol, 
triglycerides, glucose) 
X 
Every other 
week  
Start of cycle  
Start of each cycle  
X 
Hemoglobin 
A1c 
(HbA1c)  
X  
 
Start of cycle  
With Disease 
Evaluations in 
Courses 4 and 6 and 
after every 4 courses 
thereafter  
X 
Blood tests for 
cholesterol, 
triglycerides and 
function of the 
pancreas 
(amylase/lipase) 
X 
Weekly 
Start of cycle 
Start of each cycle 
X 
Pregnancy test 
(All females10 years 
of age and older) 
X 
 
Start of cycle 
Start of each cycle 
 
Heart rhythm test 
(EKG)  
X 
One hour after 
day 1 treatment 
is finished 
End of cycle 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
Neuropsychological 
Testing  
Within one week 
before starting 
treatment 
End of cycle 
End of cycle 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
 Neuropsychological 
evaluation with 
licensed psychologist 
for patients less than 
3 years of age 
Within one week 
before and up to 
two weeks after 
starting 
treatment  
 
End of cycle 
End of cycle 6, 10 
and then every 8 
cycles thereafter 
X 
Submit Patient 
Treatment Diaries 
 
X 
X 
X 
X 
Blood for Lorlatinib 
drug level tests (PK - 
Required) 
 
Day 1: 3 times 
Day 2: 1 time 
Day 15: 5 times 
 
 
 
Blood for circulating 
tumor cells (Optional) 
X 
 
With disease evaluation 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
 

Bone Marrow 
Aspirate (Optional) 
X 
 
With disease evaluation 
End of cycle (4,6, 
and every 4th cycle 
thereafter) 
 
Sampling of leftover 
tumor tissue 
(Optional) 
Leftover tumor tissue can be sent at any time during the study 
 
Tests done at Disease Evaluation 
Bone marrow 
aspirate and biopsy 
X 
 
Week 4 
 
End of cycle (4,6 
and every 4th cycle 
thereafter) 
X 
CT/MRI scans and/or 
MIBG/PET scans 
Blood and bone 
marrow for NANT 
Biology study# 
# Patients enrolled in the companion biology study may have additional samples of blood and bone marrow collected at study entry 
and with each disease evaluation time point. Please look at the biology study (NANT 2004-05) consent form for more information. 
**Blood draws can be done more often if needed at the discretion of your study doctor 

Consent Addendum II 
Certificate of Confidentiality Information 
 
NANT 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. 
 

APPENDIX VIII: DOSE EXPANSION COHORT A2: PATIENTS > 18 YEARS OF AGE SAMPLE 
CONSENT 
 
NANT 2015-02:  PHASE 1 STUDY OF LORLATINIB, AN ORAL SMALL MOLECULE INHIBITOR OF 
ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY NEUROBLASTOMA 
 
COHORT A2: PATIENTS 18 YEARS OF AGE AND OLDER  
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol. 
 
WHAT IS THIS STUDY ABOUT? 
This study is a clinical trial, a type of research study. Clinical trials include only patients who choose to take 
part. Please take your time to make your decision about participating. You may discuss your decision with 
your friends, family, and health care team. If you have any questions, you may ask your doctor. 
 
You are being asked to participate in this study because you have a kind of cancer called neuroblastoma. 
It may be that your cancer went away for a while but has grown back (relapsed) or it may be that it has 
never gone away (persistent or resistant tumor) after standard treatment. Standard treatment may have 
included chemotherapy, surgery, radiation therapy, high-dose chemotherapy with a stem cell transplant 
and/or immunotherapy. 
 
WHY IS THIS STUDY BEING DONE? 
 
The Purposes Of This Study Are: 
 
• 
To find the highest dose of lorlatinib that can be given to adults with refractory or relapsed 
neuroblastoma without causing severe side effects.  
 
• 
To learn about the side effects of the drug lorlatinib when given to adults. 
 
• 
To determine if your tumor gets smaller after treatment with lorlatinib. 
 
• 
To measure the levels of lorlatinib in the blood  
 
• 
To look at genetic changes in tumor DNA found in the blood during treatment. 
 
• 
To look at genetic changes in tumor tissue to see if they affect response to lorlatinib. 
 
• 
To describe the amount of neuroblastoma tumor found in the blood and bone marrow by testing 
samples with a new test (called NB5 assay). 
 
The Research Is Being Done Because: 
Currently there is no known effective treatment for your type of cancer.  We are testing new experimental 
drugs such as lorlatinib in the hopes of finding a drug that may be effective against neuroblastoma tumors 
that have come back (relapsed) or that have never gone away (persistent/refractory) after treatment with 
standard therapy.  
 
This study involves the use of an experimental drug called lorlatinib.  In laboratory testing, lorlatinib blocks the 
Anaplastic Lymphoma Kinase (ALK) gene. ALK may be important in the growth of certain types of cancer 
cells such as neuroblastoma.  Lorlatinib is considered experimental because it has not been proven to work 
in a situation like yours.  Lorlatinib has been approved by the United States Food and Drug Administration 
(FDA) to treat adults with non-small cell lung cancer, a different cancer than yours.It is not approved for 
neuroblastoma.  Lorlatinib has been used only in a small number of adults so there is a lot we do not know 
about it yet.  In these previous studies, the recommended dose of lorlatinib that can be given safely was 

determined for adults. In this study, we are also studying higher dose levels. Adults will receive 2 dose 
levels of lorlatinib on this cohort. All patients enrolled on this study are known to have a defect in the ALK 
gene in their tumor before they start treatment.   
 
In this study, the lorlatinib dose you will be given is higher than the recommended dose given to adults with 
other cancers who have been treated with lorlatinib.  This is because based on laboratory studies, it is 
thought that higher levels of lorlatinib might be needed to have an effect on neuroblastoma.  Other adults 
have been treated at similar higher dose levels in the past and side effects experienced were temporary 
and resolved after stopping or decreasing the dose of lorlatinib.  You will be closely monitored for any side 
effects with this treatment.    
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
There will be about 60-75 patients enrolling on the 4 study cohorts. You have been given this consent 
because the planned enrollment is on cohort A2. When you join the study, you will be assigned a certain 
lorlatinib dose. Cohort A2 will test up to 2 lorlatinib doses. There will be a a minimum of 20 patients enrolling 
on these two doses. Investigators are trying to decide the highest dose of lorlatinib that can be given without 
bad side effects.  
 
WHAT WILL HAPPEN TO ME IF I TAKE PART IN THIS STUDY? 
 
Before You Begin the Study  
Your doctor will have previously sent your tumor for genetic testing and these results showed your tumor 
has a defect in the ALK gene which allows you to be considered for participation in this study. 
 
You will need to have the following exams, tests or procedures to find out if you can take part in the study. 
Most of these exams, tests or procedures are part of regular cancer care and may be done even if you do 
not join the study. These tests will also be done at various times throughout the study and at the end of the 
study.  The purpose of these tests is to see how well the treatment works and to measure the status of your 
neuroblastoma. If you have had some of them recently, they may not need to be repeated. This will be up 
to your doctor. 
 
A medical history & physical exam 
Bone marrow tests3 to check your tumor 
Blood tests1 
Various scans4 to check your tumor 
Pregnancy test (urine or blood)2 
Electrocardiogram (EKG) to check the heart rhythm5 
 
Neuropsychological testing6 
 
1Some blood tests (cholesterol and fat digestion [triglycerides]) may need to be done on an empty stomach, 
so you cannot eat or drink anything other than water for 8-10 hours before these tests are done (called 
fasting).   Your doctor or nurse will tell you if it is necessary for you to fast before these blood tests are 
done. 
 
2If you are a female at least 10 years old or who could have children, you will have a pregnancy test done 
by the doctor the week before starting treatment and then before each cycle of treatment begins. Both you 
and your parent/legal guardian (if applicable) will be informed of a positive pregnancy test.  All men and 
women who could have children must either agree to practice abstinence from heterosexual intercourse or 
use two effective methods of birth control for as long as they participate in this study.  
 
3Bone marrow tests are done by inserting a needle into the hip bone to remove the marrow which is inside 
the bone. 
 
4Various scans are done for diagnosis and checking the response of the tumor to treatment. These may 
include CT and /or MRI scans and MIBG or PET scans. We will recommend scans specific for your case 
and we will answer your questions about these scans. 

5Electrocardiogram (EKG) to document your heart rhythm before beginning lorlatinib treatment.  
 
6Central nervous system effects (speech, memory and mood changes) were seen in previous studies 
treating adults with Lorlatinib.  Neuropsychological testing will be done at within one week of starting 
treatment and at different times during this study to monitor for any changes in thinking skills, behavior and 
mood.   Please see the section on Neuropsychological testing below in “During this Study” for more details 
on what tests are done and when they are done during this study.  
 
During the Study   
If the exams, tests and procedures show that you can be in the study, and you choose to take part, lorlatinib 
will be given for 28 days.  This entire period is called a cycle with each treatment cycle being 28 days long.  
You may continue to take lorlatinib for an unlimited number of cycles unless you develop serious side effects 
or your tumor worsens. 
 
Lorlatinib will be given by mouth once a day followed by a small glass of water.  If you vomit lorlatinib within 
20 minutes of taking the dose for the day, that dose can be repeated.  This is the only time a dose of 
lorlatinib can be repeated.  
 
Lorlatinib will be available as a tablet.  If you are unable to swallow the tablets whole, you will be instructed 
on how to make a liquid lorlatinib solution at home by mixing the lorlatinib tablets with water and a flavoring 
agent (Ora-Plus®).  Your nurse or doctor will help you decide what is best for you and will make sure you 
have the proper directions for taking this medication. 
 
You will be given a patient diary at the beginning of each cycle of lorlatinib.  Use the diary to record the date 
and time you take the drug, all vomited and missed doses, side affects you experience and any other 
medications and supplements you are taking.  The diary should be returned to clinic along with the 
medication bottle (even if it is empty) weekly during cycle 1 and then after each treatment cycle of lorlatinib.  
This will help us to know how much of the drug you take and how it made you feel. 
 
During the study you will have tests and procedures done to check for side effects from taking lorlatinib and 
to see how your tumor is doing.  Many of these tests are part of regular cancer care but you may have them 
done more often because you are on the study: 
 
Physical exam 
Electrocardiogram (EKG) to test heart rhythm3 
Blood tests1 
Bone marrow tests & various scans (CT/MRI, MIBG or 
PET) to check your tumor4 
Pregnancy test (urine or blood)2 
Neuropsychological testing5 
 
1Some blood tests (cholesterol and fat digestion) can only be done on an empty stomach, so patients cannot 
eat or drink anything other than water for 8-10 hours before these tests are done.   
 
2A urine or blood pregnancy test will be done before each treatment cycle begins if you are a female who 
could have children. Both you and your parent/legal guardian will be informed of a positive pregnancy test. 
One Treatment Cycle  
 (Cohort A2: adults and children/adolescents higher BSA group meeting adult dosing 
criteria) 
Week 1 
Week 2 
Week 3 
Week 4 
Days 1 - 7 
Days 8 – 14 
Days 15 - 21 
Days 22 - 28 
 
Lorlatinib once a day 
 

All men and women who could have children must continue to practice abstinence from heterosexual 
intercourse or use two effective methods of birth control for as long as they participate in this study.  
 
3Electrocardiogram (EKG) done before starting study treatment will be repeated at certain times during the 
study to document if lorlatinib treatment has any effect on heart rhythm. 
 
4Bone marrow tests and various scans are done for checking the response of your tumor to treatment.  
These tests will be done at certain times during the study to look at response to lorlatinib and check that 
your tumor has not gotten worse. 
 
5Neuropsychological Testing 
Neuropsychological evaluations try to understand how changes in the health of the brain may affect 
behavior or mood and how well a person is able to pay attention, remember things or solve problems.  Since 
effects on speech, memory and mood were seen in a small number of adults receiving lorlatinib, 
neuropsychological testing will be done to monitor for changes in thinking skills, behavior and mood at 
different times during this study.  A table at the end of the consent lists how often neuropsychological testing 
will be done during the study.  Testing methods are based on the age of the patient and include 
computerized tests using an iPad, written questionnaires and evaluations by a licensed psychologist.  
Parents or legal guardians of patients less than 18 years of age will also participate by completing written 
questionnaires at the same time their child is being tested.   
 
The results of the neuropsychological testing will be told to your doctor and entered as part of your medical 
record. Neuropsychological results will be used to make decisions about your care while enrolled on this 
study.  If the testing results show areas of concern, you may be given more frequent testing as well as 
referrals for other care if needed.  During testing, patients may skip questions that are stressful and may 
stop taking the tests at any time.  Testing can be done as part of the clinic visit.  You will need to talk with 
your doctor and nurse about scheduling to do these tests at times that are workable for you and your child. 
 
• 
Patients 18 years of age and older will complete computerized tests using an iPad and their own 
written questionnaires.  Parents/Legal guardians do not have testing to do with patients of this age. 
 
 
Patient age at 
testing in years 
Testing being done 
Length of testing time  
for Patients 
Length of testing time for 
Parents/legal guardians 
1 
Patient: licensed psychologist 
Parent/legal guardian: written 
questionnaires 
~ 60 - 90 minutes 
~ 20 minutes 
2 
~ 50 minutes 
3 - 5 
Patient: computerized tests using an 
iPad 
Parent/legal guardian: written 
questionnaires 
~ 10 minutes 
~ 50 minutes 
6 
~ 30 – 40 minutes 
~ 50 minutes 
7 - 9 
~ 30 – 40 minutes 
~ 50 - 55 minutes 
10 - 17 
~ 35 – 45 minutes 
~ 50 - 55 minutes 
18 – 25 
Patient: computerized tests using an 
iPad and written questionnaires 
~ 80 - 90 minutes 
NA 
26+ 
 
 
 
 
 
 
 
 

NANT Biology Study (NANT 2004-05) 
You will also be expected to join a companion NANT biology study to collect blood, bone marrow and tumor 
tissue (if available) and reports from radiology scans from patients with neuroblastoma. The biology study 
also provides a place (called NANT biorepository) where any leftover samples of tumor tissue or bone 
marrow and blood collected on this study could be transferred and stored. While you will be asked to join 
the Biology Study (NANT 2004-05), the decision to store/bank any leftover samples is optional and will not 
affect your ability to participate in this treatment study with Lorlatinib.  Your doctor will talk with you in detail 
about the NANT biology study and have you sign a separate consent form. 
 
Additional Tests in this Study 
We would like to do some extra tests called pharmacokinetic studies and biologic studies.  These tests will 
help us learn more about lorlatinib and may help children and adolescents 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 meaning you can decide whether you 
want to do them or not.  
 
Pharmacokinetic Studies:  Determining Blood Levels of Lorlatinib – Required 
During this study blood samples will be collected to determine how much lorlatinib is in your blood (called 
pharmacokinetics). About 3mL (just over half a teaspoon) of blood will be drawn with each sample.  A total of 
9 blood samples will be obtained over 3 separate days during course 1 (Day 1, Day 2 and Day 15).  The total 
amount of blood drawn for testing will be about 27 mL (almost 5 ½ teaspoons). If you have a central line (such 
as a port or a Broviac) these samples can be drawn through that line or through a small tube placed in a vein 
in your hand or arm.  This amount of blood is considered safe to donate. Samples will be sent to a commercial 
laboratory contracted to perform these tests for the study. These samples will be the property of Pfizer and 
Pfizer may also use the PK Biological Samples for evaluation of the bioanalytical method. 
 
Other Biology Research Tests in this Study – Optional 
You will be asked if you want to participate in 3 optional research tests.  You can decide not to let the doctors 
do these tests and still be able to be treated as part of this study.  There are checkboxes at end of this form 
to mark whether you are willing to participate in these voluntary studies. The results of these research tests 
will not be shared with you or become part of your medical record.  These results would also not be used to 
make decisions about your care while enrolled on this study.    
 

• 
Using extra blood to look for genetic changes seen in tumor cells. 
Tumor cells often release small pieces of DNA into the blood stream where it can be detected by 
sensitive tests.  About 17mL (almost four teaspoons) of blood will be drawn at study entry and at 
each time disease evaluation testing is done (after cycles 2, 4, 6 and then every 4th cycle) to look at 
what genetic changes in your tumor may be seen over time from the small pieces of tumor DNA 
found in your blood. The blood will be sent to a commercial laboratory contracted to perform this 
testing for the study. 
 
• 
Comparing genetic changes between leftover tumor from an earlier procedure (diagnosis or 
second look) to relapsed neuroblastoma tumor tissue and bone marrow aspirates and 
whether these changes affect how the tumor will respond to treatment with Lorlatinib. 
Researchers would like to look at tumor tissue to determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  These tests 
would be done on tumor tissue remaining from diagnosis, or any previous surgery where tumor 
tissue was removed (removal of primary tumor or removal of tumor at a relapse) in the past. The 
tissue and bone marrow aspirates will be sent to a research laboratory at Children’s Hospital of 
Philadelphia for testing.   
 
When you have finished treatment with Lorlatinib  
After you stop treatment on this study, you will continue to have tests and scans done (listed below) to 
measure how much tumor is left. If test results show you have abnormal organ functions, tests are 
recommended by the study to be repeated monthly until test results are stable or normal. You doctor will 
tell you how often these tests and evaluations will be done. 
 
Medical Tests after the Study: 
 
Physical exam  
Neuropsychological testing1 
Blood tests 
Bone marrow tests and Various scans (CT/MRI, MIBG or 
PET) to check your tumor2 
Electrocardiogram (EKG) to 
check the heart rhythm3 
 
 
1The same neuropsychological testing and evaluation done before starting study treatment will be done at 
the end of treatment with lorlatinib.  The need for any further testing after this will be up to your doctor. 
 
2Bone marrow tests and various scans are done for checking the response of your tumor to treatment.  
These tests will be done at the end of a course and at certain times following treatment to monitor your 
tumor status. 
 
3 Electrocardiogram (EKG) done at the end of the study to document if lorlatinib treatment has any effect 
on heart rhythm.  
 
A table detailing the tests and procedures required before, during and after the study has been attached to 
the end of this form (Consent Addendum 1). 
 
HOW LONG WILL I BE ON THIS STUDY?  
You can get an unlimited number of treatment cycles with lorlatinib as long as you are not having bad side 
effects and as long as your tumor is not getting worse.   
 
After you stop treatment, you will continue to have tests and scans done to measure how much tumor is left. 
Your doctor will tell you how often these tests will be done. Researchers will continue to collect information 
about you for a lifetime. Information will be collected about whether you are still alive; whether your tumor has 
grown back and at what sites in the body; whether you have developed any side effects from the treatment; 

or whether you have developed any additional cancer. Your oncologist or family doctor will give the 
researchers this information at regular intervals. 
 
CAN I STOP BEING IN THE STUDY? 
Yes. If you are thinking about stopping your participation on this study, you should talk to your doctor before 
making a final decision so he/she can tell you how to do this safely.  
 
Your doctor may also stop you from taking part in this study at any time if he/she believes it is in your best 
interest; if you do not follow study rules; or if the study is stopped. 
 
WHAT ARE THE RISKS OF THE STUDY? 
This is a Phase 1 study.  A Phase 1 study looks at how common and serious side effects can be for each 
patient at a specific dose of a drug. In a Phase 1 study, some patients may have very serious side effects 
and could die as a result of these side effects. You may be one of those patients who have serious side 
effects as a result of participating in this Phase 1 study.  
 
In this study, researchers will be looking at side effects seen in patients taking different doses of lorlatinib. 
Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know 
all the side effects that may happen. Side effects may be mild or very serious. Other drugs may be given 
to make side effects less serious and more comfortable (such as for nausea, headache or reaction to 
lorlatinib). Many side effects go away soon after you stop taking the study medications but it is always 
possible that side effects can be serious, long lasting or may never go away. There is also a risk of death. 
Patients are watched carefully and treatment will be stopped if bad side effects develop. There may also 
be risks we do not know about. You should talk to your doctor about any side effects that you have while 
taking part in this study.  
 
While on the study, you are at risk for the side effects listed 
 below: 
 
Possible Risks of Lorlatinib 
 
The following side effects are considered to be related to lorlatinib have been reported:  
Very Common  
(may affect 10 or more in 100 people) 
Common 
(may affect from 1 up to less than 10 in 100 people) 
• 
Increase in cholesterol and triglycerides 
(fats in your blood)  
• 
Effects on mood (for example, irritability 
and mood swings)  
• 
Effects on memory (for example, 
confusion, memory loss and disturbance 
of attention)  
• 
Effects on the peripheral nerves which are 
those outside of the brain and spinal cord, 
including tingling, numbness or pain in 
hands and feet)  
• 
Changes in vision (including double 
vision, perceived flashes or floaters of 
light, light intolerance, vision blurred, 
• 
Hallucination and loss of contact with 
reality 
• 
Changes in mental status  
• 
Changes in speech (for example, slow 
speech or slurred speech) 
• 
Inflammation of the lungs (pneumonitis) 
which can cause shortness of breath and 
difficulty breathing. If severe, this can be 
life threatening.  
 
 
 
 

vision sharpness reduced and visual 
impairment) 
• 
Hypertension  
• 
Diarrhea  
• 
Constipation  
• 
Joint pain  
• 
Build-up of fluid in the body or extremities 
causing swelling (edema)  
• 
Fatigue (feeling tired and exhausted)  
• 
Increase in body weight 
• 
Increase in blood sugar levels 
 
 
The following events have also been reported in patients while they were taking lorlatinib, although the 
relationship to lorlatinib is uncertain:  
 
Very common (may affect 10 or more in 100 people) 
• 
Abnormalities in blood tests that may indicate liver damage 
• 
Abnormal pancreas tests 
• 
Decrease in hemoglobin in the blood that can cause weakness 
• 
Headache 
• 
Muscle pain 
• 
Difficulty sleeping 
• 
Rash 
 
Common (may affect from 1 up to less than 10 in 100 people) 
• 
Decrease of ejection fraction of the heart which may indicate severe heart problem 
• 
A sudden and temporary loss of consciousness (syncope) 
• 
Changes in the electrical activity of your heart that might lead to a heart rhythm problem and/or 
irregular heartbeat 
 
Uncommon (may affect less than 1 in 100 people) 
• 
Inflammation of the pancreas causing pain in the upper abdomen. This could become severe and 
may cause nausea and vomiting, fever and rapid heart rate. This could require hospitalization and 
may be life threatening 
• 
Suicidal thoughts 
• 
Psychosis 
 
Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised 
when driving or operating machines as patients may experience CNS effects.  
 
 
 
 
z 

  Possible Risks to Unborn Child 
Patients who agree to participate in this study should not become pregnant while on this study. Lorlatinib 
may cause fetal harm when administered to a pregnant woman and is not recommended during 
pregnancy or for women of childbearing potential not using contraception. Women of childbearing 
potential should use nonhormonal methods of birth control. If a hormonal method of birth control is 
unavoidable, then a condom must be used in combination with the hormonal method. Female patients 
must continue to follow these birth control guidelines for 21 days after finishing the study. Male patients 
must wear condoms as one of their forms of birth control for the duration of the study and for 97 days 
after finishing the study. Further contraception use should be discussed with your personal physician. If 
you or your partner becomes pregnant while you are participating in this study, please notify your doctor 
immediately.  For more information about risks and side effects, ask your doctor. 
 
Possible Long Term Side Effects of Treatment with Lorlatinib 
Side effects in adults treated with lorlatinib have occurred while patients have been receiving the drug or 
shortly after finishing the drug.  It is not known if some side effects may be seen only after a long time after 
finishing treatment with lorlatinib.   
 
Possible Risks from Having Blood Drawn 
The risks from having your blood taken are minimal, but can include an infection or a blood clot. Experienced 
doctors or nurses will perform these blood draws to minimize this risk.   
 
Unknown Risks 
The treatment may have side effects that no one knows about yet.  The researchers will let you know if they 
learn anything that might make you change your mind about participating in the study. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
There may or may not be direct medical benefit to you. The information learned from this study may or may 
not benefit other children, young people and adults with solid cancers in the future. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
There are other options for you instead of this treatment. Instead of being in this study, you have these 
options: 
 
• 
Treatment with other chemotherapy medicines  
• 
Treatment with other experimental agents that may be available. 
• 
No neuroblastoma therapy at this time, with care to help you feel more comfortable. 
Please talk about these options with your doctor. 
 
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. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance and data 
analysis include: 
• 
New Approaches to Neuroblastoma Therapy (NANT) Consortium at Children’s Hospital Los 
Angeles in Los Angeles, CA.  The NANT Consortium identifies you by a number. 
• 
Independent auditor evaluating quality assurance for the NANT Consortium. 
• 
The National Cancer Institute (NCI) and other governmental agencies, like the Food and Drug 
Administration (FDA) or Health Canada, involved in keeping research safe for people. 
• 
Foundation Medicine, Inc. who is a collaborator on this study.  
• 
Pfizer Inc., the pharmaceutical company which makes lorlatinib. 

NANT has received a Certificate of Confidentiality from the federal government, which will help us 
protect the privacy of our research subjects. Information about the certificate is included at the end 
of this consent. 
 
Because this study involves the treatment of a medical condition, a copy of this consent form will be placed 
in your medical record. This will allow the doctors that are caring for you to obtain information about what 
medications or procedures you are receiving in the study and treat you appropriately. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
Taking part in this study may lead to added costs to your insurance company.  Your health insurance 
company will be billed for many expenses associated with the costs of this study.  These expenses include 
medications, treatments, hospital charges, and doctors’ fees related to your participation in this study.   
 
Lorlatinib and the flavoring agent (Ora-Plus®) are being provided free of charge for use in this study, but 
the costs associated with administering the drug is normally covered by your insurance company.  The cost 
of doing a heart test called an EKG and neuropsychological testing at several time points during your 
participation in the study with lorlatinib is being done solely as part of research and will be paid for by the 
study.   
 
The special research blood and tissue studies will be done at no cost to you.  However, you or your health 
plan may need to pay for the costs of the supplies and personnel who draw the blood from you for these 
tests. 
  
You may have to pay for other things during this study, such as but not limited to, your time, the cost of 
food you buy while you are being treated at the hospital, car fare, travel to and from the hospital for 
treatment, parking, and baby sitter fees. 
 
Taking part in this study may lead to added costs that may not be covered by your insurance company. 
Please ask about any expected added costs or insurance problems. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s 
website at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .  You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this website. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that 
you have been injured because of taking part in this study. You can tell the doctor in person or call him/her 
at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study. You and/or your 
health plan will be charged for this treatment.  The study will not pay for medical treatment.  
 
WHAT ARE MY RIGHTS AS A STUDY PARTICIPANT? 
Taking part in this study is your choice. You may choose not to take part or not take part in the study. If you 
decide to take part in this study, you may remove yourself from 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. If you 
remove yourself from the study, we will still take care of you. We will explain what stopping the treatment 
may do and we will offer other treatments if they are available.  
 

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 case of injury resulting from this study, you do not lose any of you legal rights to seek payment by signing 
this form. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing data from this 
research throughout the study.  We will tell you about new information from this Board or other studies that 
may affect your health or willingness to stay in the study. 
 
 
 
WHO IS FUNDING THIS RESEARCH STUDY? 
This study is supported by Pfizer, Inc. Pfizer is a drug company that makes the drug being studied in this 
research project. Pfizer is giving money to Children's Hospital for some of the costs of the study. The results 
of the study will be reported to Pfizer. If the study shows that lorlatinib may be useful for a new purpose, 
this could benefit Pfizer financially. 
 
The Children’s Hospital Los Angeles/NANT is also providing funding for this study. 
 
Dr. Mossé at Children’s Hospital of Philadelphia, one of the principal investigators of this study, has served 
as a paid consultant to Pfizer. Her participation in this research has been reviewed and approved, subject 
to management, according to CHOP’s/NANT Conflict of Interest Policy.  
 
 
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).  
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the NCI’s Cancer Information Service at 
 
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615 
 
You may visit the NCI Web sites 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/ 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you.  At most, the website will include a 
summary of the results.  You can search this website at any time. 
 
You will get a copy of this consent form. If you want more information about this study, ask your doctor. 
 
 

CONSENT FOR EXTRA STUDIES FOR RESEARCH  
 
The following tests are optional for all patients in the study. You may still participate in the study 
even if you do not agree to these tests. 
 
1. 
Using extra blood to look for genetic changes seen in tumor cells 
 
Initial next to YES if you agree to let researchers take almost 4 extra teaspoons (17 mL) at study entry 
and each time a disease evaluation is done)  to look at what genetic changes in your tumor can be 
seen in your blood over time before and after treatment with lorlatinib.  This blood would be drawn at 
a time when blood was being drawn for clinical purposes.  The blood will be sent to Foundation 
Medicine Inc. for analysis who is a collaborator on this study. The results of these tests will be 
confidential and not made available to you or your treating physician. 
 
Initial next to NO, if you do not want researchers to take extra blood above what is needed for 
clinical purposes. 
 
_______Yes 
_______No    
 
2. 
Comparing genetic changes between tumor leftover from an earlier procedure (diagnosis or 
second look) to relapsed neuroblastoma tumor tissue and bone marrow aspirates and 
whether these changes affect how the tumor will respond to treatment with Lorlatinib. 
 
Initial next to YES, if you agree (and if there is tumor remaining)  to let this tumor be sent to a laboratory 
so researchers can compare these samples and determine if there are certain gene changes present 
that might make your neuroblastoma more or less likely to respond to the drug lorlatinib.  The results 
of these tests will be confidential and not made available to you or your treating doctor. 
 
Initial next to NO if you do not want left over tumor from an earlier procedure to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely 
to respond to the drug lorlatinib. 
 
_______Yes 
_______No    
 
 
Initial next to YES, if you agree to let extra bone marrow aspirates be collected to be sent to a 
laboratory so researchers can compare these samples and determine if there are certain gene 
changes present that might make your neuroblastoma more or less likely to respond to the drug 
lorlatinib.  The results of these tests will be confidential and not made available to you or your treating 
doctor. 
 
Initial next to NO if you do not want these bone marrow aspirates collected to be sent to a research 
laboratory to look for certain gene changes that might make your neuroblastoma more or less likely 
to respond to the drug lorlatinib. 
 
 
_______Yes      _______No   
 
 
 
 
 
 
 
 

STATEMENT OF CONSENT 
 
I have already read the information in this informed consent document. I have read all the attachments 
that were included with this informed consent document. I have asked all of my questions and I have 
gotten answers. I agree to enroll myself (my child) in this study. 
 
 
______________________________________ 
Print Patient Name 
 
 
_______________________________________ 
 
_____/_____/_____ 
Signature of Patient  
 
 
 
 
 
 
Date 
 
 
_______________________________________ 
 
_____/_____/______ 
Signature of Physician or  
 
 
 
 
 
Date 
Responsible Investigator 
 
_______________________________________ 
 
____/_____/______ 
Signature of Witness 
 
 
 
 
 
 
Date 
 
 
_______________________________________ 
 
____/_____/______ 
Signature of Translator  
 
 
 
 
 
Date 

Consent Addendum I: Tests that will be done on this study. 
 
Observation 
Before Entry 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of 
Therapy 
Physical exam including 
neurological exam 
X 
Weekly 
Start of cycle 
Start of each cycle 
X 
Routine blood tests** 
(Blood counts, electrolytes, liver, kidney 
function, , function of pancreas- 
amylase/lipase) 
X 
Weekly  
Weekly for blood 
counts and twice 
during cycle for all 
other blood tests   
Start of each cycle 
X 
Routine Blood tests** 
(Fasting cholesterol, triglycerides, 
glucose) 
X 
Every other week  
Start of cycle  
Start of each cycle  
X  
Hemoglobin A1c (HbA1c)  
X 
 
Start of cycle  
With Disease Evaluations in 
Courses 4 and 6 and after 
every 4 cycles thereafter  
X  
Pregnancy test 
(All females 10 years of age and older) 
X 
 
Start of cycle 
Start of each cycle 
 
Heart rhythm test 
(EKG)  
X 
One hour after 
day 1 treatment is 
finished 
End of cycle 
End of cycle (4,6 and every 
4th cycle thereafter) 
X 
Neuropsychological Testing  
 
Within one week 
before starting 
treatment 
End of cycle 
End of cycle 
End of cycle (4, 6 and every 
4th cycle thereafter) 
X 
Neuropsychological evaluation with 
licensed psychologist for patients 
less than 3 years of age 
Within one week 
before and up to 
one week after 
starting 
treatment 
 
End of cycle 
End of cycle 6, 10 and then 
every 8 cycles thereafter 
X 
Submit Patient Treatment Diaries 
 
X 
X 
X 
X 
Blood for Lorlatinib drug level tests 
(PK - Required) 
 
Day 1: 3 times 
Day 2: 1 time 
Day 15: 5 times 
 
 
 
Bone Marrow Aspirate (Optional) 
X 
 
With disease 
evaluation 
End of cycle (4,6, and every 
4th cycle thereafter) 
 
Blood for circulating tumor cells 
(Optional) 
X 
 
With disease 
evaluation 
End of cycle (4,6 and every 
4th cycle thereafter) 
 
Sampling of leftover tumor tissue 
(Optional) 
Leftover tumor tissue can be sent at any time during the study 
 
Tests done at Disease Evaluation 
Bone marrow aspirate and biopsy 
X 
 
Week 4 
End of cycle (4,6 and every 
4th cycle thereafter) 
X 
CT/MRI scans and/or MIBG/PET 
scans 
Blood and bone marrow for NANT 
Biology study# 
# Patients enrolled in the companion biology study may have additional samples of blood and bone marrow collected at study entry 
and with each disease evaluation time point. Please look at the biology study N04-05 consent form for more information. 
**Blood draws can be done more often if needed at the discretion of your study doctor 

Consent Addendum 2 
Certificate of Confidentiality Information 
 
NANT 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. 

APPENDIX IX:  SAMPLE ASSENT FORM COHORTS A1 AND B1 
 
NANT 2015-02:  PHASE 1 STUDY OF PF-06463922 (LORLATINIB), AN ORAL SMALL MOLECULE 
INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY 
NEUROBLASTOMA 
 
Cohorts A1 and B1:  Taking Lorlatinib only 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol  
 
INVESTIGATOR 
[Insert Name of Investigator] 
[Insert Name of Institution] 
 
[Insert Address (include City, State and Zip Code)]  
[Insert Telephone/Fax Numbers] 
[Insert Email] 
 
 
1.  Dr. _______________ is doing a research study about using other medicines to get rid of 
Neuroblastoma.  
 
2.  You have a kind of cancer called neuroblastoma. We are doing a study about this kind of cancer. It 
may be that your cancer went away for a while but has come back. Or it may be that it has never gone 
away. We are asking you to take part in a research study because doctors want to learn more about 
treating neuroblastoma using a medicine called lorlatinib to see what effects (both good and bad) this 
medicine has on patients and their cancer.  Lorlatinib is a medicine that is given by mouth either as a 
pill (tablet) or a liquid.  The doctors think that giving this drug may help get rid of neuroblastoma cancer 
cells.   
 
3. If you agree to be in this study this is what will happen: 
You will take lorlatinib by mouth every day followed by a small glass of water.   Lorlatinib is given in 
cycles that last about one month (28 days).  You can continue taking lorlatinib for as many cycles as you 
can unless there are side effects or your tumor gets worse.  Lorlatinib works differently than some of the 
other medicines you have gotten before to treat your neuroblastoma.    Before this study started, the 
doctors sent a sample of your tumor to a laboratory for testing and found out there is a change in the 
ALK gene.  The ALK gene is a gene that when it has been changed, can help your neuroblastoma tumor 
to grow.  Lorlatinib works on the ALK gene.  Researchers hope it will stop your neuroblastoma tumor 
from growing.   
 
Coming to See the Doctors: 
During and after you have finished the treatment, you will have appointments with the doctors who are 
taking care of you. This is called “Follow-Up”.  This is to see how well the treatment has worked so far. 
The doctors will want to do some special tests to find this information out. They will include; 
 
  
• 
Blood tests (we will do this twice each week to start with, and then less often).  You may need 
to fast (not eat anything and not drink anything other than water) for 8 hours before certain 
blood tests.  This will happen once per week in the first month of treatment and then just once 
per month during the rest of treatment.  
• 
A heart test called an EKG that shows the doctors your heart beat.  This is done by attaching 
wires from an EKG machine to your chest with sticky pads.  It takes less than 5 minutes to 
do this test once all the wires are attached. 
• 
MRI, CT, and MIBG Scans (special pictures of your tumor) 
• 
Bone marrow test (to look for tumor in your bone marrow) 
• 
Feel your belly, look into your eyes and ears, and listen to your heart and lungs. 
• 
Ask you and your parents a lot of questions about how you are feeling, how you are doing in 
school, and any problems you might be having.   

o 
The doctors will have you answer questions about how you are doing using an iPad.  
This should take about 30 minutes to do.  At the same time you are using your iPad; 
your parents will also answer questions about how you are doing using pen and 
paper.  This testing will be done at the beginning then monthly to every other month 
for a year then less often after that.  Your doctor will let you know if any of these 
testing needs to be done more often. 
• 
You will come to visit your doctor every week or so to start with, then less often if everything 
is going well.  
• 
To measure the amount of medicine in your blood, we will draw 9 blood samples (about 5 
teaspoons total) over the first 2 days of treatment with lorlatinib.  We can use your central 
line to draw these blood samples.  If you don’t have a central line, you will need to have a 
needle poke or a small plastic tube placed in a vein of your hand or arm to collect these 
samples.  
 
4. When you are in a research study, sometimes good things and bad things can happen. 
Sometimes things happen to kids in research studies that may make them feel bad.  These are called 
“risks”.  Some of the risks of this study are:  
• 
You may feel lightheaded, jittery, irritable or hungry while you are fasting before certain tests  
• 
You may have swelling in your arms and legs 
• 
You may have tingling, or prickly feeling or numbness in your hands and feet 
• 
You may have a hard time concentrating, remembering things or talking to others. 
• 
You may feel tired 
• 
You may feel sick to your stomach and you may throw up 
• 
You may not feel like eating 
•   You may get diarrhea or constipation 
•   You may feel difficulty breathing  
•   You may gain weight  
• 
The treatments may not work and your tumor may grow, or it might come back again after the 
treatment has finished.  If this happens, we will try other ways to stop the tumor from growing. 
• 
You could get a different kind of cancer, this doesn’t happen often, but can happen years later. 
• 
It is possible you could die from the treatment or cancer. 
 
Not all of these things may happen to you. It’s possible that none of them will happen. Or bad things may 
happen that we don’t know about yet.  
• 
Things that happen to children in research studies that are good are called “benefits”.  Some of 
the good things for this research study could be: 
o 
This treatment might make your neuroblastoma tumor stay the same size or get smaller 
for some time. 
o 
We hope to learn more about this new treatment which could help other children with 
neuroblastoma 
 
5. We will do everything possible to keep your information private and prevent people outside of the study 
from seeing information about you.  
 
6. Please talk this over with your parents before you decide whether or not to be in this study. We will also 
ask your parents to give their permission for you to take part in this study.  But even if your parents 
say “yes” you can still decide not to do this.   
 
7. You do not have to be in this study if you don’t want to. You may stop being in this study at any time. 
Remember, being in this study is up to you.  
 
8. You can ask any questions that you have about the study. If you have a question later that you didn’t 
think of now, you can call me or ask me next time you see me.   
 

o Study doctor’s phone number: __________________ 
 
9. Special Study Tests:  
You will have blood tests done to measure the amount of lorlatinib in your blood.  This blood test will 
be done 9 times over 3 days in the first course. A central line can be used to draw these blood samples.  
Otherwise you may need to have a needle poke or a small plastic tube placed in a vein of your hand or 
arm for these samples. 
 
There are extra tests on this study that are optional meaning that you can say no to doing these tests 
and still be part of the main study.  Please discuss this with your family. These extra tests are done for 
research only so the results won’t be told to your doctor or to you. 
 
#1:   
Almost 4 teaspoons of extra blood will be taken at the same time blood will be drawn as part 
of your  normal neuroblastoma care.  This would be done when you start the study and then 
every time after when you have tests and scans to look at how your tumor is doing (called a 
disease evaluation). 
 
 
#2:  
The doctors will compare old and new tumor samples and bone marrow aspirates collected 
from you as part of your normal neuroblastoma care.  They will be looking at changes in the 
ALK gene in these tumor samples. 
 
 
 
Signing your name at the bottom means that you agree to be in this study.   You and your parents will be 
given a copy of this form after you have signed it. 
 
Name of Patient: _________________________ 
 
 
 
 
 
 
 
 
 
_______ Yes, I want to be in the study. 
 
______     No, I do not want to be in the study. 
 
________________________________________ 
_____________________ 
Signature of Patient 
 
 
 
 
 
Date 
 
________________________________________ 
_____________________ 
Name of Physician or Responsible Investigator 
 
Date 
 
_____________________________________  
______________________ 
Signature of Physician or Responsible Investigator  
Date  
 
 

APPENDIX X:  SAMPLE ASSENT FORM COHORT A2 
 
NANT 2015-02:  PHASE 1 STUDY OF PF-06463922 (LORLATINIB), AN ORAL SMALL MOLECULE 
INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY 
NEUROBLASTOMA 
 
Cohort A2:  Taking Lorlatinib only 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol  
 
INVESTIGATOR 
[Insert Name of Investigator] 
[Insert Name of Institution] 
 
[Insert Address (include City, State and Zip Code)]  
[Insert Telephone/Fax Numbers] 
[Insert Email] 
 
 
1. Dr. _______________ is doing a research study about using other medicines to get rid of 
Neuroblastoma.  
 
2. You have a kind of cancer called neuroblastoma. We are doing a study about this kind of cancer. 
It may be that your cancer went away for a while but has come back. Or it may be that it has never 
gone away. We are asking you to take part in a research study because doctors want to learn more 
about treating neuroblastoma using a medicine called lorlatinib to see what effects (both good and 
bad) this medicine has on patients and their cancer.  Lorlatinib is a medicine that is given by mouth 
either as a pill (tablet) or a liquid.  The doctors think that giving this drug may help get rid of 
neuroblastoma cancer cells.   
 
2. If you agree to be in this study this is what will happen: 
You will take lorlatinib by mouth every day followed by a small glass of water.   Lorlatinib is given in 
cycles that last about one month (28 days).  You can continue taking lorlatinib for as many cycles as 
you can unless there are side effects or your tumor gets worse.  Lorlatinib works differently than some 
of the other medicines you have gotten before to treat your neuroblastoma.    Before this study started, 
the doctors sent a sample of your tumor to a laboratory for testing and found out there is a change in 
the ALK gene.  The ALK gene is a gene that when it has been changed, can help your neuroblastoma 
tumor to grow.  Lorlatinib works on the ALK gene.  Researchers hope it will stop your neuroblastoma 
tumor from growing.   
 
Coming to See the Doctors: 
During and after you have finished the treatment, you will have appointments with the doctors who 
are taking care of you. This is called “Follow-Up”.  This is to see how well the treatment has worked 
so far. The doctors will want to do some special tests to find this information out. They will include; 
 
  
• 
Blood tests (we will do this twice each week to start with, and then less often).  You may need 
to fast (not eat anything and not drink anything other than water) for 8  hours before certain 
blood tests.  This will happen once per week in the first month of treatment and then just once 
per month during the rest of treatment.  
• 
A heart test called an EKG that shows the doctors your heart beat.  This is done by attaching 
wires from an EKG machine to your chest with sticky pads.  It takes less than 5 minutes to 
do this test once all the wires are attached. 
• 
MRI, CT, and MIBG Scans (special pictures of your tumor) 
• 
Bone marrow test (to look for tumor in your bone marrow) 
• 
Feel your belly, look into your eyes and ears, and listen to your heart and lungs. 

• 
Ask you and your parents a lot of questions about how you are feeling, how you are doing in 
school, and any problems you might be having.   
o 
The doctors will have you answer questions about how you are doing using an iPad.  
This should take about 30 minutes to do.  At the same time you are using your iPad; 
your parents will also answer questions about how you are doing using pen and 
paper.  This testing will be done at the beginning then monthly to every other month 
for a year then less often after that.  Your doctor will let you know if any of these 
testing needs to be done more often. 
• 
You will come to visit your doctor every week or so to start with, then less often if everything 
is going well.  
• 
To measure the amount of medicine in your blood, we will draw 9 blood samples (about 5 
teaspoons total) over the first 2 days of treatment with lorlatinib.  We can use your central 
line to draw these blood samples.  If you don’t have a central line, you will need to have a 
needle poke or a small plastic tube placed in a vein of your hand or arm to collect these 
samples.  
 
3. When you are in a research study, sometimes good things and bad things can happen. 
Sometimes things happen to kids in research studies that may make them feel bad.  These are called 
“risks”.  Some of the risks of this study are:  
a. You may feel lightheaded, jittery, irritable or hungry while you are fasting before certain 
tests  
b. You may have swelling in your arms and legs 
c. You may have tingling, or prickly feeling or numbness in your hands and feet 
d. You may have a hard time concentrating, remembering things or talking to others. 
e. You may feel tired 
f. 
You may feel sick to your stomach and you may throw up 
g. You may not feel like eating 
h. You may get diarrhea or constipation 
i. 
You may feel difficulty breathing 
j. 
You may gain weight 
k. The treatments may not work and your tumor may grow, or it might come back again 
after the treatment has finished.  If this happens, we will try other ways to stop the tumor 
from growing. 
l. 
You could get a different kind of cancer, this doesn’t happen often, but can happen years 
later. 
m. It is possible you could die from the treatment or cancer. 
 
Not all of these things may happen to you. It’s possible that none of them will happen. Or bad things 
may happen that we don’t know about yet.  
• 
Things that happen to children in research studies that are good are called “benefits”.  Some of 
the good things for this research study could be: 
o 
This treatment might make your neuroblastoma tumor stay the same size or get smaller 
for some time. 
o 
We hope to learn more about this new treatment which could help other children with 
neuroblastoma 
 
4. We will do everything possible to keep your information private and prevent people outside of the 
study from seeing information about you.  
 
5. Please talk this over with your parents before you decide whether or not to be in this study. We will 
also ask your parents to give their permission for you to take part in this study.  But even if your 
parents say “yes” you can still decide not to do this.   
 
6. You do not have to be in this study if you don’t want to. You may stop being in this study at any 
time. Remember, being in this study is up to you.  

 
7. You can ask any questions that you have about the study. If you have a question later that you 
didn’t think of now, you can call me or ask me next time you see me.   
o Study doctor’s phone number: __________________ 
 
8. Special Study Tests:  
You will have blood tests done to measure the amount of lorlatinib in your blood.  This blood test will 
be done 9 times over the 3 days in the first course.   A central line can be used to draw these blood 
samples.  Otherwise you may need to have a needle poke or a small plastic tube placed in a vein of 
your hand or arm for these samples. 
 
There are extra tests on this study that are optional meaning that you can say no to doing these tests 
and still be part of the main study.   These extra tests are done for research only so the results won’t 
be told to your doctor or to you. 
 
#1:   
Almost 4 teaspoons of extra blood will be taken at the same time blood will be drawn as part 
of your  normal neuroblastoma care.  Please discuss this with your family. This would be done 
when you start the study and then every time after when you have tests and scans to look at 
how your tumor is doing (called a disease evaluation). 
 
#2:  
The doctors will compare old and new tumor samples and bone marrow aspirates collected 
from you as part of your normal neuroblastoma care.  They will be looking at changes in the 
ALK gene in these tumor samples. 
 
 
Signing your name at the bottom means that you agree to be in this study.   You and your parents will be 
given a copy of this form after you have signed it. 
 
Name of Patient: _________________________ 
 
 
 
_______ Yes, I want to be in the study. 
______     No, I do not want to be in the study. 
 
________________________________________ 
_____________________ 
Signature of Patient 
 
 
 
 
 
Date 
 
________________________________________ 
_____________________ 
Name of Physician or Responsible Investigator 
 
Date 
 
_____________________________________  
______________________ 
Signature of Physician or  
 
 
 
 
Date  
Responsible Investigator 
 
 
 

APPENDIX XI:  SAMPLE ASSENT FORM COHORT B2 
 
NANT 2015-02:  PHASE 1 STUDY OF PF-06463922 (LORLATINIB), AN ORAL SMALL MOLECULE 
INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY 
NEUROBLASTOMA 
 
Cohort B2:  Taking Lorlatinib combined with chemotherapy (cyclophosphamide/topotecan) 
 
A New Approaches to Neuroblastoma Therapy (NANT) treatment protocol  
 
INVESTIGATOR 
[Insert Name of Investigator] 
[Insert Name of Institution] 
 
[Insert Address (include City, State and Zip Code)]  
[Insert Telephone/Fax Numbers] 
[Insert Email] 
 
 
1.  Dr. _______________ is doing a research study about using other medicines to get rid of 
Neuroblastoma.  
 
2.  You have a kind of cancer called neuroblastoma. We are doing a study about this kind of cancer. It 
may be that your cancer went away for a while but has come back. Or it may be that it has never gone 
away. We are asking you to take part in a research study because doctors want to learn more about 
treating neuroblastoma using three experimental medicines called lorlatinib, cyclophosphamide 
and topotecan  and to see what effects (both good and bad) these medicines has on patients and 
their cancer.  Lorlatinib is a medicine that is given by mouth either as a pill (tablet) or a liquid.  
Cyclophosphamide and topotecan are medicines that are given into the bloodstream either through 
your central line or a small tube placed in a vein in your hand or arm.  The doctors think that giving 
these three drugs together may help get rid of neuroblastoma cancer cells.   
 
3. If you agree to be in this study this is what will happen: 
 
The medicines will be given in cycles that each last about one month (28 days).  Your doctor will explain 
the schedule for each cycle to you and your parents.  You can continue to get this treatment unless you 
have bad side effects or your tumor gets worse.  These medicines work differently than some of the 
other medicines you have gotten before to treat your neuroblastoma.  
 
Before this study started, the doctors sent a sample of your tumor to a laboratory for testing and found 
out there is a change in the ALK gene.  The ALK gene is a gene that when it has been changed, can 
help your neuroblastoma tumor to grow.  Lorlatinib works on the ALK gene.  Researchers hope it will 
stop your neuroblastoma tumor from growing when used together the chemotherapy medinces 
cyclophosphamide and topotecan.   
 
Lorlatinib: 
You will take lorlatinib by mouth every day followed by a small glass of water.    
 
Cyclophosphamide and topotecan: 
You will take cyclophosphamide and topotecan by I.V. once a day for the first 5 days of every cycle. You 
will be in the clinic on those days.  You do not need to be in the hospital to get these chemotherapy 
medicines. 
 
 
 
 
 
 

Other medicines (not chemotherapy): 
You will need to take Neupogen (given once a day as an injection) or Neulasta (given once each 
 
cycle as an injection).  These medicines are given to help your normal blood cells get better after 
 
getting chemotherapy medicines like cyclophosphamide and topotecan. 
 
Coming to See the Doctors: 
During and after you have finished the treatment, you will have appointments with the doctors who are 
taking care of you. This is called “Follow-Up”.  This is to see how well the treatment has worked so far. 
The doctors will want to do some special tests to find this information out. They will include; 
 
  
• 
Blood tests (we will do this twice each week to start with, and then less often).  You may need 
to fast (not eat anything and not drink anything other than water) for 8 hours before certain 
blood tests.  This will happen once per week in the first month of treatment and then just once 
per month during the rest of treatment.  
• 
A heart test called an EKG that shows the doctors your heart beat.  This is done by attaching 
wires from an EKG machine to your chest with sticky pads.  It takes less than 5 minutes to 
do this test once all the wires are attached. 
• 
MRI, CT, and MIBG Scans (special pictures of your tumor) 
• 
Bone marrow test (to look for tumor in your bone marrow) 
• 
Feel your belly, look into your eyes and ears, and listen to your heart and lungs. 
• 
Ask you and your parents a lot of questions about how you are feeling, how you are doing in 
school, and any problems you might be having.   
o 
The doctors will have you answer questions about how you are doing using an iPad.  
This should take about 30 minutes to do.  At the same time you are using your iPad; 
your parents will also answer questions about how you are doing using pen and 
paper.  This testing will be done at the beginning then monthly to every other month 
for a year then less often after that.  Your doctor will let you know if any of these 
testing needs to be done more often. 
• 
You will come to visit your doctor every week or so to start with, then less often if everything 
is going well.  
• 
To measure the amount of medicine in your blood, we will draw 9 blood samples (about 5 
teaspoons total) over the first 2 days of treatment with lorlatinib.  We can use your central 
line to draw these blood samples.  If you don’t have a central line, you will need to have a 
needle poke or a small plastic tube placed in a vein of your hand or arm to collect these 
samples.  
 
4. When you are in a research study, sometimes good things and bad things can happen. 
Sometimes things happened to children in research studies that may make them feel bad.  These are 
called “risks”.  Some of the risks of this study are:  
• 
You may feel lightheaded, jittery, irritable or hungry while you are fasting before certain tests  
• 
You may have swelling in your arms and legs 
• 
You may have tingling, or prickly feeling or numbness in your hands and feet 
• 
You may have a hard time concentrating, remembering things or talking to others. 
• 
You may feel tired 
• 
You may feel sick to your stomach and you may throw up  
• 
You may not feel like eating  
• You might have a fever and maybe an infection where you will need to be in the hospital to get 
medicines to treat the infection.  You may feel tired and weak and need a blood transfusion 
or you may get bruises or have bleeding (most often a nosebleed) and need a platelet 
transfusion. 
• You may get sores in your mouth that makes it difficult to eat and drink.  If this happens, you 
may need some pain medicines and you may need to stay in the hospital. 
• You may get diarrhea or constipation. 

• You may feel difficulty breathing 
• You may gain weight 
• 
The treatments may not work, and your tumor may grow, or it might come back again after the 
treatment has finished. If this happens we will try other ways to stop the tumor from growing  
• 
You could get a different kind of cancer, this doesn’t happen often, but can happen years later 
• 
It is possible that you could die from the treatment or cancer  
 
Not all of these things may happen to you. It’s possible that none of them will happen. Or bad things 
may happen that we don’t know about yet.  
 
Things that happen to children in research studies that are good are called “benefits”.  Some of the 
good things for this research study could be: 
• 
This treatment might make your neuroblastoma tumor stay the same size or get smaller for some 
time. 
• 
We hope to learn more about this new treatment which could help other children with 
neuroblastoma 
 
5. We will do everything possible to keep your information private and prevent people outside of the study 
from seeing information about you.  
 
6. Please talk this over with your parents before you decide whether or not to be in this study. We will also 
ask your parents to give their permission for you to take part in this study.  But even if your parents 
say “yes” you can still decide not to do this.   
 
7. You do not have to be in this study if you don’t want to. You may stop being in this study at any time. 
Remember, being in this study is up to you.  
 
8. You can ask any questions that you have about the study. If you have a question later that you didn’t 
think of now, you can call me or ask me next time you see me.   
 
o Study doctor’s phone number: __________________ 
 
9. Special Study Tests:  
You will have blood tests done to measure the amount of lorlatinib in your blood.  This blood test will 
be done 9 times over 3 days in the first course.   A central line can be used to draw these blood samples.  
Otherwise you may need to have a needle poke or a small plastic tube placed in a vein of your hand or 
arm for these samples. 
 
There are extra tests on this study that are optional meaning that you can say no to doing these tests 
and still be part of the main study. Please discuss this with your family.  These extra tests are done for 
research only so the results won’t be told to your doctor or to you. 
 
#1:   
Almost 4 teaspoons of extra blood will be taken at the same time blood will be drawn as part 
of your  normal neuroblastoma care.  This would be done when you start the study and then 
every time after when you have tests and scans to look at how your tumor is doing (called a 
disease evaluation). 
 
 
#2:  
The doctors will compare old and new tumor samples and bone marrow aspirates collected 
from you as part of your normal neuroblastoma care.  They will be looking at changes in the 
ALK gene in these tumor samples. 
 
 
 
 

 
 
Signing your name at the bottom means that you agree to be in this study.   You and your parents will be 
given a copy of this form after you have signed it. 
 
 
Name of Patient: _________________________ 
 
 
 
 
 
 
 
 
 
 
_______ Yes, I want to be in the study. 
 
______     No, I do not want to be in the study. 
 
 
 
________________________________________ 
_____________________ 
Signature of Patient 
 
 
 
 
 
Date 
 
 
________________________________________ 
_____________________ 
Name of Physician or Responsible Investigator 
 
Date 
 
 
_____________________________________  
______________________ 
Signature of Physician or  
 
 
 
 
Date  
Responsible Investigator