NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of Palbociclib in Patients With Tumors Harboring Activating Alterations in Cell Cycle Genes
Phase: PHASE2
Conditions: Advanced Malignant Solid Neoplasm, Recurrent Childhood Ependymoma, Recurrent Ewing Sarcoma, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Kidney Wilms Tumor, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Refractory Ependymoma, Refractory Ewing Sarcoma, Refractory Glioma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma
Sponsor: National Cancer Institute (NCI)

Group Chair 
Douglas S. Hawkins, MD 
Seattle Children's Research  
Institute 
doug.hawkins@seattlechildrens 
.org  
 
Group Vice Chair 
Lia Gore, MD 
Children's Hospital Colorado 
lia.gore@cuanschutz.edu  
 
Group Statistician 
Todd Alonzo, PhD 
talonzo@childrensoncology 
group.org 
 
Executive Director of Clinical  
Research Operations 
Mary Beth Sullivan, MPH 
msullivan@childrensoncology 
group.org  
 
Executive Director of 
Data Operations 
Thalia Beeles, MPH 
tbeeles@childrensoncology 
group.org 
 
Executive Director of 
Administration and Finance 
Jennifer Bandich, MBA 
jbandich@childrensoncology 
group.org 
 
Group Operations Center  
and 
Statistics & Data Center  
(SDC) Headquarters 
800 Royal Oaks Drive 
Suite 210 
Monrovia, CA 91016 
P 626 241 1500 
F 626 445 4334 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A National Cancer Institute- 
funded group member of the  
National Clinical Trials Network 
 
 
i 
 
 
November 30, 2021 
 
 
 
 
 
 
 
 
 
Martha Kruhm, M.S., RAC 
Protocol and Information Office (PIO) Head 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
Please find attached Amendment #4 to APEC1621I, NCI-COG Pediatric MATCH 
(Molecular Analysis for Therapy Choice)- Phase 2 subprotocol of Palbociclib in Patients 
with Tumors Harboring Activating Alterations in Cell Cycle Genes. 
 
The protocol and ICD have been amended in preparation for Stage 2 of Pediatric 
MATCH. Descriptions of screening and enrollment procedures have been revised to align 
with Amendment #4 of APEC1621SC to implement Stage 2.  
 
Several other administrative changes have been made; specific changes are detailed 
below. Minor administrative updates (such as the correction of typographical errors or 
updates to the numbers of referenced sections) are tracked in the protocol but not 
specified below. 
 
Please contact us if you have any further questions. 
 
Sincerely, 
 
Lee Baker, MPH, Protocol Coordinator (for) 
Rajen Mody, MD, APEC1621I Study Chair, and 
Douglas S. Hawkins, MD, Group Chair, Children’s Oncology Group 
 
 
 

 
ii 
 
 
SUMMARY OF CHANGES 
The following specific revisions have been made to the protocol and informed consent 
document. Additions are in boldfaced font and deletions in strikethrough font. 
# 
Page(s) 
Section 
Change 
1. 
Through
out 
Throughout 
• 
Updated version date and amendment number. 
• 
Ensured all hyperlinks are present and functioning 
2. 
2 
Contact 
Information 
Included, as this is part of the most recently approved template. 
3. 
5-6 
Study 
Committee 
Updated COG operations staff information for the PC, RC and master 
statistician. 
4. 
7 
Abstract 
To be consistent with the stage 2 process amendment #4 for APEC1621SC, 
removed language about performing the assay for genomic profiling and 
replaced with the process to identify aMOI’s for subprotocol placement.  
5. 
14 
3.1 
Updated language to most recently approved templated language. 
6. 
14-16 
3.1.1 
 
3.1.2 
 
3.1.3 
To be consistent with the stage 2 process amendment #4 for APEC1621SC, 
language has been revised to include the MRC review process of pathology 
results to review potential mutations for eligibility in subprotocol therapies. 
7. 
17 
3.5 
To be consistent with the stage 2 process amendment #4 for APEC1621SC, 
revised enrollment periods for treatment assignment to 2-weeks 
8. 
18 
4.1.1 
Included language to reference the process for identifying aMOIs as defined in 
AMD #4 for APEC1621SC. 
9. 
18 
4.1.4 
The definition of measurable disease for CNS tumors was updated to match the 
definition in Section 12 
10. 
26 
8.1 
Patient Diary has been revised to Medication Dairy 
11. 
29 
8.3.1 
Revised language to state that ctDNA samples are requested, but not required. 
This is consistent with AMD #4 of APEC1621SC Stage 2.  
12. 
53 
13.1.1 
Included new templated language for expediated adverse event reporting. 
13. 
54 
13.1.2 
Updated fax number for NCI and email for COG for reporting expedited AEs. 
14. 
66 
Appendix II 
CYP3A4 appendix updated. 
15. 
69 
Appendix III Title of appendix has been changed from Patient Diary for Palbociclib to 
Medication Diary for Palbociclib 
16. 
81 
Appendix 
VIII 
Included “Examples of” and “for APEC1621I” in the title of this appendix. 
17. 
82-83 
Appendix 
IX 
Updated youth information sheets to reflect new language 
18. 
84-87 
Appendix X 
Updated appendix, in accordance with the most recently approved templated 
language. 

 
iii 
 
 
SUMMARY OF CHANGES: ICD 
In accordance with the above discussion, the following specific revisions have been made to the protocol. 
Additions are in boldfaced font and deletions in strikethrough font. 
 
# 
Section 
Comments 
19. 
Throughout 
• 
Updated version date. 
• 
Ensured all hyperlinks are included and functioning. 
20. 
Why am I 
being invited 
to take part 
in this study? 
Revised language to be consistent with AMD #4 of APEC1621SC, where tumor tissue pathology 
results are reviewed by the Molecular Review Committee (MRC) for eligibility into the subprotocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
                     . 
APEC1621I 
 
                                                                                                                      
Page 1 
Version Date: 11/30/2021 
Activated:06/25/2018 
 
Version Date: 11/30/2021 
 
Closed: 
 
Amendment#  4 
 
 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
APEC1621I 
 
NCI-COG PEDIATRIC MATCH 
(MOLECULAR ANALYSIS FOR THERAPY CHOICE)- 
PHASE 2 SUBPROTOCOL OF PALBOCICLIB IN PATIENTS WITH TUMORS HARBORING 
ACTIVATING ALTERATIONS IN CELL CYCLE GENES 
 
 
Open to COG Member Institutions in the USA  
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED 
OR USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN 
THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY 
ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT 
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL 
HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
STUDY CHAIR 
Rajen Mody, MD 
CS Mott Children’s Hospital 
1500 East Medical Center Drive 
D4202 MPB 
Ann Arbor, MI 48109-5718 
Phone: 734-232-9335 
Email: rmody@med.umich.edu

 
                       
APEC1621I 
 
                                                                                                                      
Page 2 
Version Date: 11/30/2021 
 
 
Contact Information 
For Regulatory Requirements 
For patient enrollments: 
For Data Submission 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
 (Sign in at www.ctsu.org, and 
select the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment section 
of the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://open.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or email:  
1-888-823-5923, or  ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. Please 
see the Data Submission 
Schedule in the CRF packet for 
further instructions. 
The most current version of the study protocol must be downloaded from the protocol-specific page located on the 
CTSU members’ website (https://www.ctsu.org). Access to the CTSU members’ website is managed through the 
Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and 
requires log in with a CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the CTSU Regulatory 
Support System (RSS). 
For clinical questions (ie, patient eligibility or treatment-related)  
Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (ie, unrelated to patient eligibility, treatment, or clinical data submission)  
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will be 
triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 
 
 
 

 
                       
APEC1621I 
 
                                                                                                                      
Page 3 
Version Date: 11/30/2021 
TABLE OF CONTENTS 
SECTION 
PAGE 
 
CHILDREN’S ONCOLOGY GROUP 
1 
STUDY COMMITTEE 
5 
STUDY COMMITTEE, CONT. 
6 
COG OPERATIONS STAFF 
6 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
 
Primary Aims 
8 
 
Secondary Aims 
8 
 
Exploratory Aims 
8 
2.0 
BACKGROUND 
8 
 
Introduction/Rationale for Development 
8 
 
Preclinical Studies 
10 
 
Adult Studies 
11 
 
Pediatric Studies 
13 
 
Overview of Proposed Pediatric Study 
13 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
14 
 
Genetic Screening Procedures for Eligibility 
Error! Bookmark not defined. 
 
IRB Approval 
15 
 
Informed Consent/Assent 
17 
 
Screening Procedures 
17 
 
Eligibility Checklist 
17 
 
Study Enrollment 
17 
 
Institutional Pathology Report 
17 
 
Dose Assignment 
17 
4.0 
PATIENT ELIGIBILITY 
18 
 
Inclusion Criteria 
18 
 
Exclusion Criteria 
21 
5.0 
TREATMENT PROGRAM 
22 
 
Overview of Treatment Plan 
22 
 
Criteria for Starting Subsequent Cycles 
23 
 
Grading of Adverse Events 
23 
 
Definition of Dose-Limiting Toxicity (DLT) 
23 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
24 
 
Dose Modifications for Hematological Toxicity 
24 
 
Dose Modifications for Non-Hematological Toxicity 
24 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
25 
 
Concurrent Anticancer Therapy 
25 
 
Investigational Agents 
25 
 
Supportive Care 
25 
 
Growth Factors 
25 
 
Concomitant Medications 
25 

 
                       
APEC1621I 
 
                                                                                                                      
Page 4 
Version Date: 11/30/2021 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
25 
 
Required Clinical, Laboratory and Disease Evaluation 
25 
 
Radiology Studies 
27 
 
Circulating Tumor DNA Study (optional) 
28 
9.0 
AGENT INFORMATION 
30 
 
Palbociclib (Ibrance®, PD-033299, 571190-30-2) 
30 
NSC# 772256 
30 
 
Agent Ordering and Agent Accountability 
34 
 
Clinical Drug Request and Investigator Brochure Availability 
35 
 
Agent Inventory Records 
35 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
36 
 
Criteria for Removal from Protocol Therapy 
36 
 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
36 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
36 
 
Sample Size and Study Duration 
36 
 
Dosing Considerations 
36 
 
Study Design 
36 
 
Methods of Analysis 
37 
 
Evaluability for Response 
38 
 
Evaluability for Toxicity 
38 
 
Progression free survival (PFS) 
38 
 
Correlative Studies 
38 
 
Gender and Minority Accrual Estimates 
38 
12.0 
EVALUATION CRITERIA 
39 
 
Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
39 
 
Progression-Free Survival 
39 
 
Response Criteria for Patients with Solid Tumors 
39 
 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
43 
 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
45 
 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
47 
 
Response Criteria for Patients with CNS Tumors 
48 
 
Response Criteria for Patients with Lymphoma/Histiocytosis 
50 
 
Best Response 
51 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
52 
 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
52 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
54 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements:
 
56 
 
Definition of Onset and Resolution of Adverse Events 
56 
 
Other Recipients of Adverse Event Reports 
57 
 
Specific Examples for Expedited Reporting 
57 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
59 
 
Categories of Research Records 
59 
 
CDUS 
59 
 
CRADA/CTA/CSA 
59 
 
Data and Safety Monitoring Plan 
61 

 
                       
APEC1621I 
 
                                                                                                                      
Page 5 
Version Date: 11/30/2021 
REFERENCES 
62 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
65 
APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
66 
APPENDIX III:  PATIENT DIARY FOR PALBOCICLIB 
69 
APPENDIX IV: PALBOCICLIB DOSING NOMOGRAM 
72 
APPENDIX V: APEC1621I THERAPY DELIVERY MAP 
73 
APPENDIX VI CORRELATIVE STUDIES 
79 
APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621I EXPANSION COHORTS 
80 
APPENDIX VIII: APEC1621I ACTIONABLE MUTATIONS OF INTEREST 
81 
APPENDIX IX APEC1621I YOUTH INFORMATION SHEETS 
82 
APPENDIX X CTEP AND CTSU REGISTRATION PROCEDURES 
84 
APPENDIX XI PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
88 
APPENDIX XII TOXICITY-SPECIFIC GRADING 
90 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
                      THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
APEC1621I 
 
                                                                                                                      
Page 5 
Version Date: 11/30/2021 
STUDY COMMITTEE 
STUDY CHAIR 
Nita Seibel, MD 
Rajen Mody, MD 
National Cancer Institute 
CS Mott Children’s Hospital 
9609 Medical Center Drive, MSC 9739 
1500 East Medical Center Drive  
Rockville, MD 20892 
D4202 MPB 
Phone:  (240) 276-6560 
Ann Arbor, MI 48109-5718 
Fax:  (240) 276-7892 
Phone: 734-232-9335 
E-mail: seibelnl@mail.nih.gov  
Fax: 734-615-0464 
 
Email: rmody@med.umich.edu 
 
 
Douglas S. Hawkins, MD 
Margaret Macy, MD 
Seattle Children’s Hospital 
Vice Chair 
Mailstop: JMB 9, 1900 9th Avenve 
Children’s Hospital of Colorado 
Seattle, WA 98101 
13123 East 16th Avenue, B115 
Phone:  (206) 884-1107 
Aurora, CO 80045 
Phone (720) 777-6458 
Email: doug.hawkins@seattlechildrens.org 
Email: Margaret.macy@childrenscolorado.org 
 
 
Stacey Berg, MD 
Will Parsons, MD, PhD 
Study Design and Logistics 
Baylor College of Medicine 
Baylor College of Medicine 
1102 Bates, Suite 1030.15 
Pediatric Oncology  
Houston, TX 77030 
6621 Fannin Street 
Phone: (832) 824-4643 
MC3-3320 
Email: dwparson@txch.org 
Houston, TX 77030 
 
Phone: (832) 824-4588 
Todd Alonzo, PhD 
Fax:  (832) 825-4039 
Study Statistician  
Email: sberg@txch.org 
COG Statistics and Data Center- Monrovia 
 
222 East Huntington Dr., Suite 100 
Elizabeth Fox, MD 
Monrovia, CA 91016 
Study Design and Logistics 
Phone: (626) 241-1522 
Saint Jude Children’s Research Hospital 
Fax: (626) 445-4334 
Cancer Center, Clinical Trials Administration 
Email: talonzo@childrensoncologygroup.org 
262 Danny Thomas Place 
 
Memphis, TN 38105 
Joel Reid, PhD. 
Phone: (901) 595-3300 
Study Pharmacologist 
Email: elizabeth.fox@stjude.org 
Mayo Clinic 
  
Guggenheim 17-37 
Jin Piao, PhD 
200 First St SW 
Study Statistician 
Rochester, MN 55905 
COG Statistics and Data Center- Monrovia 
Phone: (507) 284-0822 
222 East Huntington Dr., Suite 100 
Fax: (507) 284-3906 
Monrovia, CA 91016 
E-mail: reid.joel@mayo.edu  
Phone: (626) 241-1572 
 
Fax: (626) 445-4334 
 
Email: jpiao@childrensoncologygroup.org 
 
 
 
 

 
                      THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY. SEE PAGE 1 FOR USAGE POLICY. 
APEC1621I 
 
                                                                                                                      
Page 6 
Version Date: 11/30/2021 
STUDY COMMITTEE, CONT. 
TBD                                                      
Study CRA 
Julia Brown, PharmD  
Study Pharmacist 
 
CS Mott Children’s Hospital 
 
1540 E. Hospital Drive, Rm 10-620 
 
Ann Arbor, MI  48109 
 
Phone: (734) 647-5157 
 
E-mail:brownjdb@umich.edu 
 
 
 
COG OPERATIONS STAFF 
 
TBD 
Lauren Saguilig, MS 
Research Coordinator 
Master Statistician  
Phone: TBD 
Children’s Oncology Group – Operations Center 
 
Fax (626) 445-4334 
Lee Baker, MPH 
Scientific Writer/Protocol Coordinator 
Email: lsaguilig@childrensoncologygroup.org 
Children’s Oncology Group – Operations Center 
Phone: (626) 241-1614 
Email: lebaker@childrensoncologygroup.org 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
For Group Operations (GOC) and 
 
Statistics & Data Center (SDC) contacts see: 
 
https://members.childrensoncologygroup.org 
 
 
 
AGENT NSC# 
 
NCI-Supplied Agents: 
Palbociclib 
 
(NSC# 772256) 
 
IND Sponsor: DCTD, NCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621I 
Page 7 
Version Date: 11/30/2021 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about subjects collected during the course of our covered studies.  The 
researchers involved in the studies cannot be forced to disclose the identity or any information collected in 
the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
ABSTRACT 
This subprotocol is a component of the Pediatric MATCH trial APEC1621. The APEC1621SC screening 
protocol details the process used to identify actionable mutations in patient tumor samples will determine 
eligibility for this subprotocol. This is a phase 2 trial of palbociclib in children with relapsed or refractory 
solid tumors (including non-Hodgkin lymphomas, histiocytoses and CNS) harboring specified genomic 
alterations in the cyclinD-cdk4/6-INK4a-Rb pathway, including CDK4 or CDK6 amplification and 
CCND1, CCND2, or CCND3 amplification, along with positive Rb expression by immunohistochemistry. 
 
Palbociclib is a reversible, selective oral small molecule inhibitor of CDK 4 and 6. It arrests the cell cycle 
by blocking the progression from G1 to S phase by preventing the phosphorylation of the RB protein 
resulting in cell cycle arrest thereby inhibiting cell proliferation and cellular DNA synthesis at low 
nanomolar concentrations.1 Palbociclib’s activity is dependent on the expression of tumor suppressor 
retinoblastoma (Rb1) protein. Palbociclib was granted accelerated approval in February 2015 and received 
full FDA approval in March 2017 for the treatment of breast cancer. It has demonstrated promising 
antitumor potential as monotherapy or combined therapy in numerous clinical trials. 
 
Palbociclib will be given orally once daily on days 1-21 with 7 days off in a 28-day cycle. The pediatric 
MTD and RP2D was determined to be 75 mg/m2. 
 
EXPERIMENTAL DESIGN SCHEMA 
 
Treatment Schedule Table 
Days 1-21 
75 mg/m2 once daily palbociclib 
Days 22-28 
Rest 
Day 28 
Evaluation 
 
Palbociclib will be administered on days 1-21; a cycle will be 28 days. Evaluations will occur at the 
end of every other cycle x 3, then every 3 cycles.  
 
Therapy will be discontinued if there is evidence of progressive disease or drug related dose-limiting 
toxicity that requires removal from therapy. Therapy may otherwise continue for up to 2 years provided the 
patient meets the criteria for starting subsequent cycles (Section 5.2) and does not meet any of the criteria 
for removal from protocol therapy criteria (Section 10.0).  

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621I 
Page 8 
Version Date: 11/30/2021 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
 
Primary Aims 
 
 
To determine the objective response rate (ORR; complete response + partial 
response) in pediatric patients treated with palbociclib with advanced solid tumors 
(including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that 
harbor activating genetic alterations in cell cycle genes. 
 
 
Secondary Aims 
 
 
To estimate the progression free survival in pediatric patients treated with 
palbociclib with advanced solid tumors (including CNS tumors), non-Hodgkin 
lymphomas or histiocytic disorders that harbor activating genetic alterations in 
alterations in cell cycle genes. 
 
 
To obtain information about the tolerability of palbociclib in children and 
adolescents with relapsed or refractory cancer. 
 
 
Exploratory Aims 
 
 
To explore approaches to profiling changes in tumor genomics over time through 
evaluation of circulating tumor DNA. 
 
 
2.0 
BACKGROUND 
 
 
Introduction/Rationale for Development 
CDK4 and CDK6 (CDK4/6) encode cyclin-dependent serine-threonine kinases that form a 
complex with cyclinD to phosphorylate the pRb tumor suppressor protein, leading to 
release of bound E2F transcription factors and cell cycle progression from G1 to S phase. 
Cancer cells have many alterations that overcome the pRb-dependent restriction 
checkpoint, most commonly through either loss of pRb or other alterations that lead to 
constitutive activation of the cyclin-D-CDK4/6 complex. In fact, recent next generation 
sequencing studies suggest that this signaling pathway is the first or second most 
commonly altered in adult and pediatric tumors. 2 Examples of the three most common 
genetic alterations include (1) amplification or deregulated transcription of the CCND1 
gene, which encodes cyclinD1, (2) mutation, deletion or epigenetic inactivation of CDKNA 
loci that encodes p14ARF and p16INK4A, an inhibitor of the kinase activity of the cyclinD-
CDK4/6 complex, and (3) amplification or mutation of CDK4 or CDK6. In addition >90% 
of pediatric malignant rhabdoid tumors (MRT) harbor deletions of INI1/SMARCB1 gene 
which results in altered activity of the SNF5/SWI chromatin remodeling complex, resulting 
in dependence on cyclin D for MRT cell survival.3  There are currently three selective 
CDK4/6 inhibitors, including palbociclib (PD0332991), ribociclib (LEE011), and 
abemaciclib (LY2835219).  There are more than 60 adult clinical trials for these agents 
(one with ribociclib including pediatric subjects) and palbociclib was recently FDA-
approved for use in combination with an aromatase inhibitor in women with advanced 
estrogen receptor positive HER-2 negative breast cancer. Of note many adult clinical trials 
currently use cdk4/6 inhibitors, which have generally been shown to be cytostatic, in 
combination with other drugs, and eligibility often includes detection of a genomic 

 
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APEC1621I 
Page 9 
Version Date: 11/30/2021 
alteration in the cyclinD-cdk4/6-INK4a-Rb axis as well as intact pRb gene and/or protein.  
 
Table 1: Palbociclib selectively inhibits CDK 4 and 6 
CDK (cyclin partner) 
IC50 (uM) 
CDK4 (cyclin D1) 
0.011 
CDK4 (cyclin D3) 
0.009 
CDK6 (cyclin D2) 
0.015 
CDK2 (cyclin A) 
>5 
CDK1 (cyclin B) 
>5 
CDK5 (p25) 
>5 
 
CCND1 amplification has been reported in 30% of primary breast cancers4, however it is 
also observed in other tumors. The varying frequency of CCND1 amplification from both 
the Penn trial5 as well as TCGA6 are depicted in Table 2. 
 
Table 2: Frequencies of CCND1 Amplification in Penn Study and TCGA 
Tumor Type 
Number 
Screened 
Number 
with 
CCDN1 
Amplification from Penn 
Study  
(% positive) 
Number with SD or 
PR/Number 
Enrolled (%) 
Number 
with 
CCND1 
Amplification from 
TCGA 
(% 
positive) 
 
Breast 
143 
26 (18.2 %) 
7/17 (41%) 
79 (16.4%) 
Colon 
41 
1 (2.4%) 
0/1 (0%) 
n/a 
Esophageal 
20 
8 (40%) 
1/4 (25%) 
51 (55.4%)  
Gastric 
20 
2 (10%) 
0/1 (0%) 
18 (6.3%)  
SCC 
(Head 
& 
Neck) 
5 
2 (40%) 
0/1 (0%) 
77 (27.6%) 
Osteosarcoma 
1 
1 (100%) 
NA/0 
n/a 
Renal Cell  
1 
1 (100%) 
NE/1 
1 (0.6%) 
 
Frequency of biomarker in pediatric malignancies 
Genomic alterations leading to activation of the cyclinD-cdk4/6-INK4a network are 
commonly detected in both adult and pediatric tumors. Of note, the majority of published 
studies discussed below identified alterations using diagnostic specimens and a variety of 
different platforms.  Furthermore, these estimates of prevalence are likely to underestimate 
the frequency of alterations at recurrence. Recent data for neuroblastoma demonstrates 
evidence of new mutations at relapse as well as clonal evolution of low frequency 
alterations, including recurrence-specific deletions of the CDKN2A locus in 3 of 23 relapse 
specimens.7,8 The majority of alterations detected in diagnostic pediatric samples to date 
are due to copy number changes and not missense mutations. In a cohort of 82 
neuroblastoma patients analyzed by array CGH, SNP and expression arrays amplification 
of the 11q13 region that contains CCND1 was detected in 15% of tumors, deletion of one 
or both alleles of CDKN2A in 7 tumors and amplification of cdk4 or cdk6 loci in 3 tumors. 
Other neuroblastoma tumors without detectable cdk4/6 copy number gains showed 
elevated mRNA.9 In an independent group of 375 high risk neuroblastoma tumors 
CDK4(5%), CDK6(15%) and CCND1(19%) copy number gains were detected.10 The 
majority of these tumors stained positive for endogenous pRb.  
 
CDK4/6 or CCND1amplification was detected in 25% of supratentorial PNET and 1-5% 

 
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of medulloblastoma tumors, respectively.11  Alterations in this pathway were more frequent 
in glioblastoma12,13, with CDK4/6 amplifications in 20 of 281 tumors and more than 50% 
contained homozygous deletion of CDKN2A.13 Several reports in newly diagnosed Ewings 
sarcoma patients detect CDKN2A deletions in approximately 10% of cases, but copy 
number alterations in other members of this pathway have not been studied.14-16 In 
osteosarcoma rare CDK4 amplifications have been reported; however, the frequency of 
pRb alterations is higher than in other solid tumors (6% mutations, 40% 
deletions/structural).17-20 CDK4 amplification and protein expression have also been 
detected in small subsets of rhabdomyosarcoma.21,22 The majority of MRT have mutations 
and/or deletions in SMARCB123 and less commonly in SMARCA4.24 Germline mutations 
are detected in up to 50% of patients 
 
Consideration of specific agents 
As mentioned above these agents are cytostatic and thus, may be more effective in 
combination trials. Given the mechanism of action for these agents there is some concern 
and early pre-clinical studies to support that they might be protective or antagonistic with 
commonly used cytotoxic chemotherapy agents.25 Most adult studies now combine cdk4/6 
inhibition with other targeted agents that unlike common chemotherapies do not rely on 
effects on DNA replication/S phase. These include mTOR inhibitors in several cancers, 
MEK and BRAF inhibitors in melanoma, ALK inhibitors in NSLC, and HDM2 inhibitors 
for liposarcoma. These drugs are given orally and LEE011 has a liquid formulation in 
development. Although there is no published data supporting ability to cross the blood 
brain barrier, palbociclib efficacy has been shown for intracranial GBM xenografts26, and 
there are adult Phase II studies ongoing for CNS tumors, suggesting that patients with CNS 
tumors and metastatic lesions could be eligible for this agent. 
 
 
Preclinical Studies 
 
 
Antitumor Activity against pediatric tumors 
Palbociclib has been shown to have pre-clinical evidence of activity in CDK4/6 
mutated and retinoblastoma wild-type glioblastoma multiforme (GBM), diffuse 
intrinsic pontine gliomas (DIPG), and neuroblastoma tumor xenograft cell lines. 
10,26  Neuroblastoma is the third most common pediatric malignancy, and CCND 
1, 4, and 6 have been shown to be overexpressed in most neuroblastoma cases.27 
Palbociclib reduced cell proliferation in a large subset of neuroblastoma cell lines 
and xenograft models (12 of 17 human neuroblastoma-derived cell lines) by 
inducing cytostasis at nanomolar concentrations (mean IC50 = 307 ± 68 nmol/L in 
sensitive lines).28 
 
 
Animal Toxicology 
The toxicity profile of palbociclib was studied in rats, rabbits and dogs and 
included single and repeat dose studies, reproductive, developmental and 
genotoxicity studies. Based on the nonclinical safety studies conducted with 
palbociclib, the primary toxicities included effects on hematolymphopoietic and 
male reproductive organ tissues in rats and dogs. Additional target organ findings 
observed in rats only included altered glucose metabolism in relationship to effects 
on the pancreas with secondary findings in the eye, kidney, and adipose tissue; and 
effects on bone and actively growing incisor teeth. Palbociclib also caused effects 
on cardiovascular function, fetotoxicity in embryofetal development studies, and 
aneugenicity in genetic toxicity assessments. Other palbociclib-related findings 
were in gastrointestinal tissue, appeared as vacuolation in multiple tissues, and 

 
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included effects on the liver, kidney, adrenal gland, respiratory system, and 
coagulation times (prolonged) that were of limited severity and/or lacked 
degenerative features. 
 
 
Adult Studies 
Palbociclib is FDA approved in combination with endocrine therapy to treat patients with 
hormone receptor positive, HER2 negative metastatic breast cancer.29-31 Its side effect 
profile is consistent across a multitude of studies with neutropenia, the most common 
adverse event, occurring in approximately 50-62% of patients receiving the drug. Febrile 
neutropenia is extremely infrequent, occurring in 0-3% of patients.29-32 
 
 
Phase 1 Studies 
A Phase I clinical study was conducted to assess the pharmacokinetic profile of 
palbociclib at 75, 125, and 150 mg once daily dose levels for 21 days of 28-day 
cycle in 41 adult patients with RB-positive solid tumors (except small cell lung 
cancer or retinoblastoma) or non–Hodgkin lymphoma that were refractory to 
standard chemotherapy. Neutropenia was the only dose-limiting effect. The most 
common non-hematologic adverse events included fatigue, nausea, and diarrhea. 5 
 
A phase 1 trial in 33 adult patients with retinoblastoma protein-positive advanced 
solid tumors or non-Hodgkin lymphoma refractory to standard therapy received 
palbociclib once daily for 14 days followed by 7 days off (21-day cycle). Six 
patients had dose limiting toxicities due to neutropenia, four receiving 200 mg 
daily; two receiving 225 mg daily, therefore the maximum tolerated dose was 200 
mg daily.33 
 
Palbociclib was administered as 125 mg daily for three weeks, followed by one 
week off in a phase 1/2 clinical trial assessed the safety and tolerability in 
combination with letrozole 2.5 mg daily was conducted in twelve post-menopausal 
women with ER-positive, HER-2 negative breast cancer. The most common 
adverse events included neutropenia, leucopenia, and fatigue. Two patients 
experienced grade 4 neutropenia, one patient required a dose interruption.34 
 
 
Phase 2/3 Studies 
In a Phase-II study of palbociclib (PD0332991) in histologically confirmed, 
metastatic breast cancer positive for retinoblastoma (Rb) protein and measureable 
disease, palbociclib was shown to be efficacious in endocrine-resistant, HR(+), 
Rb-positive breast cancer.28 Palbociclib was given at 125 mg orally on days 1 to 
21 of a 28-day cycle. Thirty-seven patients were enrolled; 84% hormone-receptor 
(HR)(+)/Her2(-), 5% HR(+)/Her2(+), and 11% HR(-)/Her2(-), with a median of 2 
prior cytotoxic regimens. Two patients had partial response (PR) and 5 had stable 
disease ≥ 6 months for a clinical benefit rate (CBR = PR + 6moSD) of 19% 
overall, 21% in HR(+), and 29% in HR(+)/Her2(-) who had progressed through ≥
2 prior lines of hormonal therapy. Median PFS overall was 3.7 months [95% 
confidence interval (CI), 1.9-5.1], but significantly longer for those with HR(+) 
versus HR(-) disease (P = 0.03) and those who had previously progressed through 
endocrine therapy for advanced disease (P = 0.02). Grade 3/4 toxicities included 
neutropenia (51%), anemia (5%), and thrombocytopenia (22%). Twenty-four 
percent had treatment interruption and 51% had dose reduction, all for cytopenias. 
No biomarker identified a sensitive tumor population.29 

 
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A phase 2 clinical trial evaluated the and safety of palbociclib 125 mg daily for 3 
weeks, followed by one week off in combination with letrozole 2.5 mg daily 
compared with letrozole 2.5 mg daily monotherapy in 83 postmenopausal women 
with advanced estrogen receptor positive (ER+) and HER2-negative breast cancer 
who had not received any systemic treatment. There were 41 progression-free 
survival events in the combination group compared with 59 in the letrozole 
monotherapy group. The median progression free survival was 20.2 months in the 
combination group, and 10.2 months in the letrozole monotherapy group. Forty-
five patients (54%) of patients in the combination group reported grade 3-4 
neutropenia, compared with one patient (1%) of the patients in the letrozole 
monotherapy group. This study demonstrated that the addition of palbociclib to 
letrozole significantly improved progression-free survival in women with 
advanced estrogen receptor-positive and HER2-negative breast cancer.30 
Another phase II study in patients with CDK4-amplified liposarcoma revealed a 
66% progression free survival at 12 weeks including one CR lasting more than 2 
years in a patient with  CDK4 amplified liposarcoma.35 32 
In another Phase-II study of palbociclib in adults with advanced, metastatic 
hetatocellular carcinoma who have failed or are intolerant of first line therapy with 
sorafenib, subjects were treated with 125 mg /day palbociclib (PD-0332991), days 
1-21 of a 28-day cycle, until disease progression, unacceptable toxicity, 
withdrawal from study or death. Of the 21 pts (18 M, 3 F), all had pathologically 
confirmed Retinoblastoma-positive HCC and one patient experienced a 1 PR.35  
The major dose limiting toxicity of palbociclib is neutropenia. Median time to 
episode of neutropenia is 15 days, with a media duration of seven days. 
Myelosuppression is not due to apoptosis, rather it occurs through cell-cycle arrest, 
and is reversible with discontinuation.36 
The PALOMA3 study assessed the efficacy of palbociclib in a double blind, 
randomized control trial. 521 patients with endocrine-resistant advanced breast 
cancer were randomized to receive either palbociclib 125 mg/d for 3 weeks 
followed by 1 week off and fulvestrant 500 mg, or fulvestrant 500 mg and placebo. 
The progression-free survival in the combination group was 9.2 months, and 3.8 
months in the placebo control group. The most common adverse effects reported 
with neutropenia, leucopenia, and fatigue. Palbociclib in combination with 
fulvestrant improved progression free survival in hormone receptor positive 
advanced breast cancer that had progressed on prior endocrine compared with 
fulvestrant monotherapy.37 
 
 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
In plasma collected from patients enrolled on the Phase I trials, palbociclib 
concentrations were detectable 1 hour following oral administration. This indicates 
rapid absorption. Pharmacokinetics did not vary among the schedules or within 
each trial, and PK did not appear to be dose dependent over a dose-range from 25 
to 225 mg flat dosing.  The volume of distribution of palbociclib is 2793 L, which 
is high and indicates substantial tissue binding. The half-life of palbociclib is 25.9 
h and supports the appropriateness of once daily dosing.  Extended PK analyses 
are not available; however, the reproducible toxicity of the drug over long-term 
dosing indicates that drug accumulation is unlikely. Excretion has not been 
characterized in detail, however is predominantly non-renal given a measured renal 

 
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excretion of less than 2%. 5,33 
 
In another adult Phase 1 trial palbociclib was also absorbed slowly (mean Tmax, 4.2 
hours), the mean elimination half-life was 26.7 hours, and it demonstrated a large 
volume of distribution (mean 32411 L).33 
 
 
Pediatric Studies 
 
 
Prior Experience in Children  
Pediatric tumors such as brainstem gliomas and neuroblastomas are thought to 
have defects in cell cycle regulation. The maximum tolerated dose of palbociclib 
for pediatric patients with Rb positive, recurrent, progressive or refractory central 
nervous system tumors is being evaluated in an ongoing phase 1 clinical trial by 
Pediatric Brain Tumor Consortium (PBTC). The study is evaluating CNS tumors 
in less heavily (stratum I) pre-treated patients (pts) and the primary objectives of 
the study are to determine maximum tolerated dose (MTD), pharmacokinetics 
(PK), dose limiting toxicities (DLT), and preliminary evidence of efficacy. 
Presence of specific genomic alterations was not an eligibility requirement. 
Palbociclib was given orally daily for 21 days in a 28 day cycle for up to 2 yrs. 
Cohorts of 3-6 patients were treated at 50 (n = 3), 75 (n = 7), or 95 (n = 6) 
mg/m2/day. Among the sixteen eligible patients enrolled (median age 13.3 yrs; 
male 59%), 13 pts (76%) had either malignant glioma (n = 7) or DIPG (n = 6). 
Median number of courses received was 2 (range 1-9). Of 14 evaluable patients, 
the only DLT observed was Grade 4 neutropenia in 2/4 patients treated at 
95mg/m2/day. Other significant drug related course 1 toxicities included Grade 3 
neutropenia (n = 5) and Grade 3 lymphopenia (n = 2). The MTD was therefore 
determined to be 75 mg/m2/day. At 75 mg/m2, the median Cmax and Tmax for Course 
1 Day 1 was 94 ng/ml and 4.02 hr, respectively. The trial is currently enrolling an 
expansion cohort at 75 mg/m2 and an amendment to expand eligibility to more 
heavily pre-treated patients is underway.38 
  
There is another recent pediatric Phase I study for patients with MRT, 
neuroblastoma, or other tumors with alterations in cyclinD-cdk4/6-INK4a pathway 
using LEE011 (NCT NCT01747876) that is not yet reported. An interim abstract 
publication on the first 22 patients (mainly neuroblastoma and MRT) suggested 
there was an acceptable safety profile.39  
 
 
Pharmacology/Pharmacokinetics/Correlative Biological Studies: 
Pediatric pharmacokinetic studies are underway as a part of Phase-I PBTC study.  
  
 
Overview of Proposed Pediatric Study 
We propose a single arm phase 2 study of palbociclib monotherapy in pediatric patients 
with advanced solid tumors, non-Hodgkin lymphomas or CNS tumors that harbor genetic 
alterations in cell cycle genes, specifically CDK4, CDK6, CCND1, CCND2, or CCND3 
amplification. Palbociclib will be given orally once daily on days 1-21 with 7 days off in a 
28-day cycle at the previously determined RP2D  of 75 mg/m2.38 Evaluations will occur at 
the end of  every other cycle x 3, then every 3 cycles. Therapy will be discontinued if there 
is evidence of progressive disease or drug related dose-limiting toxicity that requires 
removal from therapy. Therapy may otherwise continue for up to 2 years provided the 
patient meets the criteria for starting subsequent cycles and does not meet any of the criteria 
for removal from protocol therapy criteria.  

 
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In the primary cohort of the study we will evaluate 20 mutation-matched (“biomarker 
positive”) evaluable patients of any histology for the primary study aim of determining the 
objective response rate (CR/PR) to the agent. If ≥ 3 patients in the primary cohort with the 
same histology show signs of objective response (CR/PR), a histology-specific biomarker 
positive expansion cohort will open after the primary cohort is completed to up to 7 
evaluable biomarker positive patients with that histology in order to allow us to estimate 
more precisely the activity in biomarker positive patients of that histology. A maximum of 
3 such histology specific, biomarker positive expansion cohorts will be permitted under 
this study.  
 
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
 
Study Enrollment 
 
Patient enrollment for this study will be facilitated using the Oncology Patient Enrollment 
Network (OPEN), a web-based registration system available on a 24/7 basis. It is integrated 
with the NCI Cancer Trials Support Unit (CTSU) Enterprise System for regulatory and 
roster data and, upon enrollment, initializes the patient position in the RAVE database. 
 
 
Access requirements for OPEN:  
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).The Oncology Patient Enrollment Network (OPEN) is a web-based registration 
system available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster 
data and with the Lead Protocol Organization (LPOs) registration/randomization systems 
or Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data 
in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:  
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website 

 
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at https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact 
the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
Please see Appendix IX for detailed CTEP and CTSU Registration Procedures 
including: registration in Registration and Credential Repository (RCR), requirements 
for site registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
 
IRB Approval 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. For CTEP and Division 
of Cancer Prevention (DCP) studies open to the National Clinical Trials Network 
(NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept the 
NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to 
the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 
network or protocol level. Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and 
Canadian sites only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  

 
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Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or 
a Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration packets, 
please see Appendix X. 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. For general (non-regulatory) questions call the CTSU General Helpdesk at: 
1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB approval 
for the study are not required to submit separate IRB approval documentation to the 
CTSU Regulatory Office for initial, continuing or amendment review. 
 
Investigators and site staff will need to be registered with CTEP and have a valid and active 
Cancer Therapy Evaluation Program-Identity and Access Management (CTEP-IAM) 
account (check at < https://ctepcore.nci.nih.gov/iam/ >). This is the same account (user id 
and password) used for credentialing in the CTSU members' web site. To perform 
registrations in OPEN, the site user must have been assigned the 'Registrar' role on the 
relevant Group or CTSU roster. OPEN can be accessed at https://open.ctsu.org or from the 
OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. Registrars 
must hold a minimum of an AP registration type.   
 
 
Genetic Screening Procedures for Eligibility  
 
Patient enrollment onto the APEC1621SC screening protocol is required. In Stage 2 of 
Pediatric MATCH (effective with Amendment #4 of APEC1621SC for patients enrolling 
on screening protocol) tumor genomic testing results from a CAP/CLIA-certified 
laboratory will be reviewed by the APEC1621SC Molecular Review Committee after 
APEC1621SC screening protocol enrollment to confirm the identification of an actionable 
Mutation of Interest (aMOI) for which a MATCH treatment subprotocol is available. 
Questions regarding interpretation of tumor testing results for potential APEC1621I study 
patients (such as whether a specific mutation would be considered actionable for the study) 
should be directed to the APEC1621SC and APEC1621I study chairs. 
 
The treatment assignment to a MATCH subprotocol (if a relevant aMOI is detected) will 
be communicated to the enrolling institution via the COG treatment assignment 
mechanism, upon which a reservation to APEC1621I will be secured by COG. 
Reservations should be withdrawn by the institution if at any point the patient indicates 
they do NOT intend to consent to participation or the site investigator indicates the patient 
will never be eligible for APEC1621I. 
 
 

 
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Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  This can be accomplished 
through the study-specific protocol.  Documentation of the informed consent for screening 
will be maintained in the patient’s research chart. Studies or procedures that were 
performed for clinical indications (not exclusively to determine eligibility) may be used for 
baseline values even if the studies were done before informed consent was obtained. 
 
 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 
into RAVE immediately following enrollment. 
 
 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Before enrolling a patient on study, the Study Chair or Vice Chair should be 
notified. Patients who give informed consent for the protocol in order to undergo screening 
for eligibility are not considered enrolled and should not be enrolled until the screening is 
completed and they are determined to meet all eligibility criteria. Study enrollment in Stage 
2 of Pediatric MATCH (effective with Amendment #4 of APEC1621SC for patients 
enrolling on screening protocol) is outlined in Section 3.1.3. 
 
Patients enrolling onto APEC1621I will have a COG ID obtained through their prior 
enrollment onto the APEC1621SC screening protocol or a prior COG study. Patients must 
be enrolled within 2 weeks (14 days) of treatment assignment. Protocol therapy must start 
no later than 7 calendar days after the date of enrollment. Patients who are started on 
protocol therapy prior to study enrollment will be considered ineligible. 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated in the eligibility section below. 
 
Note:  No starter supplies will be provided. Drug orders of palbociclib should be 
placed with CTEP after enrollment and treatment assignment to APEC1621I with 
consideration for timing of processing and shipping to ensure receipt of drug supply 
prior to start of protocol therapy. 
 
 
Institutional Pathology Report 
The institutional pathology report from the tumor specimen submitted for sequencing will 
have been uploaded into RAVE immediately following enrollment on the APEC1621 
master screening protocol.  
 
 
Dose Assignment 
The dose level 75 mg/m2/dose PO once daily will be assigned via OPEN at the time of 
study enrollment. 

 
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4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies, bone marrow biopsy and/or aspirate (when applicable) must be obtained within 14 days 
prior to start of protocol therapy (repeat the tumor imaging if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived.  All clinical and laboratory data required for determining eligibility of a patient 
enrolled on this trial must be available in the patient’s medical or research record which will 
serve as the source document for verification at the time of audit. 
 
 
Inclusion Criteria 
 
 
APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been 
given a treatment assignment to MATCH to APEC1621I based on the presence of 
an actionable mutation as defined in APEC1621SC. Examples of actionable 
mutations for APEC1621I are listed in Appendix VIII. 
4.1.1.1 In addition to the actionable mutations listed in section 4.1.1 positive Rb 
expression by immunohistochemistry is required for study enrollment.  
  
 
Age:  Patients must be  than 12 months and  21 years of age at the time of study 
enrollment. 
 
 
BSA:  Patients must have a body surface area ≥ 0.87 m2 at enrollment. 
 
 
Disease Status: Patients must have radiographically measurable disease (See 
section 12) at the time of study enrollment. Patients with neuroblastoma who do 
not have measurable disease but have MIBG+ evaluable disease are eligible. 
Measurable disease in patients with CNS involvement is defined as any lesion that 
is at minimum 10 mm in one dimension on standard MRI or CT. 
Note:  The following do not qualify as measurable disease:  
- 
malignant fluid collections (e.g., ascites, pleural effusions) 
- 
bone marrow infiltration except that detected by MIBG scan for 
neuroblastoma 
- 
lesions only detected by nuclear medicine studies (e.g., bone, gallium or 
PET scans) except as noted for neuroblastoma 
- 
elevated tumor markers in plasma or CSF  
- 
previously radiated lesions that have not demonstrated clear progression 

 
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post radiation  
- 
leptomeningeal lesions that do not meet the measurement requirements for 
RECIST 1.1. 
 
 
Performance Level:  Karnofsky  50% for patients > 16 years of age and Lansky 
 50 for patients  16 years of age (See Appendix I).  Note:  Neurologic deficits in 
patients with CNS tumors must have been relatively stable for at least 7 days prior 
to study enrollment.  Patients who are unable to walk because of paralysis, but who 
are up in a wheelchair, will be considered ambulatory for the purpose of assessing 
the performance score. 
 
 
Prior Therapy 
 
4.1.6.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g. blood count 
criteria, the patient is considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive. See https://members.childrensoncologygroup.org/
Disc/devtherapeutics/default.asp for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment. 
 
i. 
 ≥ 21 days after the last dose of cytotoxic or myelosuppressive 
chemotherapy (42 days if prior nitrosourea).  
 
 
 
b. Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days after the 
last dose of agent. See https://members.childrensoncologygroup.org/
Disc/devtherapeutics/default.asp for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 
of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment.  
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. 
 
d. Corticosteroids: See Section 4.2.2.1. If used to modify immune 
adverse events related to prior therapy, ≥ 14 days must have elapsed 
since last dose of corticosteroid. 
 
e. Hematopoietic growth factors: ≥ 14 days after the last dose of a long-
acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting 
growth factor. For growth factors that have known adverse events 
occurring beyond 7 days after administration, this period must be 
extended beyond the time during which adverse events are known to 
occur.  The duration of this interval must be discussed with the study 

 
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chair and the study-assigned Research Coordinator. 
 
f. Interleukins, Interferons and Cytokines (other than hematopoetic 
growth factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than hematopoetic growth factors) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 
days after infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 
days. 
 
h. Cellular Therapy: ≥ 42 days after the completion of any type of 
cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.) 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days after 
local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to 
 50% of the pelvis; ≥ 42 days if other substantial BM radiation. 
 
Note: Radiation may not be delivered to “measurable disease” tumor 
site(s) being used to follow response to subprotocol treatment. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG): 
≥ 
42 
days 
after 
systemically 
administered 
radiopharmaceutical therapy. 
 
 
k. Patients must not have received prior exposure to palbociclib 
ribociclib, abemaciclib or any other CDK4/6 inhibitors. 
 
 
Organ Function Requirements 
 
4.1.7.1 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC)  1000/mm3 
- 
Platelet count  100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.1.7.1.a 
(may receive transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 
not be evaluable for hematologic toxicity.  
 
4.1.7.2 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR  70ml/min/1.73 m2 or 

 
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- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
4.1.7.3 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated)  1.5 x upper limit of 
normal (ULN) for age   
- 
SGPT (ALT)  135 U/L.  (For the purpose of this study, the ULN 
for SGPT is 45 U/L.)  
- 
Serum albumin  2 g/dL. 
 
 
Patients must be able to swallow intact capsules. 
 
 
Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines.  
 
 
 
 
Exclusion Criteria 
 
 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks of 
fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy 
tests must be obtained in girls who are post-menarchal. Males or females of 
reproductive potential may not participate unless they have agreed to use an 
effective contraceptive method for the duration of study treatment. Females study 
participants of child-bearing potential and their partners, should agree to use highly 
effective forms of contraception for at least 3 weeks after the last dose of 
palbociclib. Male study participants should avoid fathering a child, donating 
sperm, and should agree to use highly effective forms of contraception for at least 
3 months after the last dose of palbociclib 
 
 
Concomitant Medications 
 
4.2.2.1 Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of 
corticosteroid (See Section 4.1.6.1.d). 
 

 
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4.2.2.2 Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
 
4.2.2.3 Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 
agents are not eligible. 
 
4.2.2.4 Anti-GVHD agents post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial. 
 
4.2.2.5 CYP3A4 Agents: Patients who are currently receiving drugs that are 
strong inducers or inhibitors of CYP3A4 are not eligible. Strong inducers 
or inhibitors of CYP3A4 should be avoided from 14 days prior to 
enrollment to the end of the study. See Appendix II for a list of agents.  
Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS 
tumors or metastases, on a stable dose, are allowed. 
 
 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
 
Patients who have received a prior solid organ transplantation are not eligible. 
 
 
Patients who in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study are not eligible. 
 
 
5.0 
TREATMENT PROGRAM 
 
 
Overview of Treatment Plan 
 
Treatment Schedule Table 
Days 1-21 
Palbociclib 75 mg/m2/dose (max 
dose 125 mg) PO once daily  
Days 22- 28 
Rest 
Day 28 
Evaluation 
 
Palbociclib will be given orally with food on Days 1-21, then rest for 7 days. Please see 
Appendix IV for the palbociclib dosing nomogram. Do not use commercial supply. 
 
A cycle of therapy is considered to be 28 days.  A cycle may be repeated up to a total 
duration of therapy of 2 years. 
 
Patients will be treated at the established pediatric MTD/RP2D which is 75 mg/m2 (up to 
125 mg) once daily. 
 
Drug doses should be adjusted based on the BSA calculated from height and weight 
measured within 7 days prior to the beginning of each cycle. If the patient vomits or misses 
a dose, an additional dose should not be taken. The next prescribed dose should be taken at 
the usual time. 
 

 
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Therapy will be discontinued if there is evidence of progressive disease or drug related 
dose-limiting toxicity that requires removal from therapy (Section 6.0). Therapy may 
otherwise continue for up to 2 years provided the patient meets the criteria for starting 
subsequent cycles (Section 5.2) and does not meet any of the criteria for removal from 
protocol therapy criteria (Section 10.0). 
 
 Therapy Delivery Map 
See Appendix V for therapy delivery map for Cycle 1 and subsequent cycles. 
 
 Intra-Patient Escalation 
Intrapatient dose escalation is not allowed. 
 
 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0 and 
eligible to continue agent administration per the requirements in section 6.0 
   
 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the current version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE).  All appropriate treatment 
areas should have access to a copy of the current version of the CTCAEv5.0.  A copy of 
the CTCAEv5.0 can be downloaded from the CTEP website (http://ctep.cancer.gov). Any 
suspected or confirmed dose-limiting toxicity should be reported immediately (within 24 
hours) to the Study Chair. 
 
 
 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to protocol therapy. Dose limiting hematological and non-hematological 
toxicities are defined differently.  
 
 Non-Hematological Dose-Limiting Toxicity 
5.4.1.1 Any Grade 3 or greater non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of less < 3 days duration 
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to 
levels that meet initial eligibility criteria or baseline within 7 days. See 
Appendix XII for values that represent thresholds between CTCAE 
grades. 
Note: For the purposes of this study the ULN for ALT is defined as 45 U/L 
regardless of baseline. 
- 
Grade 3 or 4 fever < 5 days duration. 
- 
Grade 3 infection < 5 days duration. 
- 
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to supplementation 
• 
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires treatment interruption. 
• 
Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 

 
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 Hematological dose limiting toxicity  
5.4.2.1 Hematological dose limiting toxicity is defined as: 
 
a) In patients evaluable for hematological toxicity (see Section 4.1.7.1),   
• 
Grade 4 thrombocytopenia or neutropenia, not due to malignant 
infiltration 
• 
Grade 3 thrombocytopenia that persists for ≥ 7 days 
• 
Grade 3 thrombocytopenia requiring a platelet transfusion on two 
separate days within a 7-day period 
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Neutropenia or thrombocytopenia that causes a delay of > 14 days 
between treatment cycles (e.g. platelets <100K or ANC<1000). 
 
5.4.2.2 Note: Grade 3 or 4 febrile neutropenia will not be considered a dose-
limiting toxicity. 
 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
 
 
Dose Modifications for Hematological Toxicity 
 
 
If a patient experiences hematological toxicity as defined in Section 5.4.2.1, the 
treatment will be held.  Counts should be checked every 3-4 days for 
thrombocytopenia and every other day for neutropenia during this time. If the 
toxicity resolves to meet eligibility parameters within 14 days of drug 
discontinuation, the patient may resume treatment at a reduced dose (see Appendix 
IV). 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 eligibility parameters within 14 days of drug 
discontinuation, the patient must be removed from protocol therapy. 
 
 
If hematological dose-limiting toxicity recurs in a patient who has resumed 
treatment at the reduced dose, the patient must be removed from protocol therapy. 
 
 
Dose Modifications for Non-Hematological Toxicity 
 
 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.4.1, the treatment will be held. When the toxicity resolves to meet 
eligibility parameters or baseline within 14 days of drug discontinuation, the 
patient may resume treatment at a reduced dose (see Appendix IV). 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 eligibility or baseline parameters within 14 
days of drug discontinuation, the patient must be removed from protocol therapy. 
 

 
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If the same dose-limiting toxicity recurs in a patient who has resumed treatment at 
the reduced dose, the patient must be removed from protocol therapy. 
 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. 
 
 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
 
 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. See Section 7.5 for drugs that should not be used 
concomitantly due to potential interactions with palbociclib. See below for recommendations 
on management of specific toxicities associated with palbociclib. 
 
 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. The Study Chair 
should be notified before growth factors are initiated. 
 
 
 
 
Concomitant Medications 
 
 
CYP3A4 inhibitors or inducers: Strong CYP3A4 inhibitors such as ketoconazole, 
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, 
ritonavir, saquinavir, telithromycin, voriconazole, grapefruit, and grapefruit juice 
are not permitted on study. Strong CYP3A4 inducers such as rifampin,  phenytoin, 
carbamazepine, rifabutin, rifapentine, phenobarbital, and St John’s wort are not 
permitted on study. (See Appendix II for a list of additional agents). 
 
 
Palbociclib is a weak time-dependent inhibitor of CYP3A4 in humans. The use 
of sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow 
therapeutic range should be avoided for the duration of the study, if reasonable 
alternatives exist (Appendix II).  
 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of therapy.  Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess 
eligibility.  If a post-enrollment lab value is outside the limits of eligibility, or laboratory 

 
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values are older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum  creatinine.  If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies, bone 
marrow aspirate and/or biopsy, must be obtained within 14 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary). 
 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
History                                                     
X 
Weekly 
X 
Physical Exam  with vital signs               
X 
Weekly 
X 
Height, weight, BSA                                
X 
 
X 
Performance Status                                  
X 
 
 
Pregnancy Test1                                                             
X 
 
 
CBC, differential, platelets                      
X 
Twice Weekly 
(every 3 to 4 days)2,3 
Weekly2,3 
Urinalysis                                                
X 
 
 
Electrolytes including Ca++, PO4, Mg++   
X 
Weekly 
X 
Creatinine, ALT, bilirubin                       
X 
Weekly 
X 
Albumin                                                   
X 
 
X 
Tumor Disease Evaluation4-A,4-B,4-C          
X 
 
Every other cycle x 3 then q 
3 cycles 4 
Bone Marrow Aspirate and/or 
biopsy5,6     
X6 
 
 
Medication Diary7                                                        
 
Weekly 
X 
Circulating Tumor (ctDNA)8 
 
 
Cycle 5, Day 1 and (for 
patients receiving ≥ 5 cycles 
only)  at end of Protocol 
Therapy OR disease 
progression  
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 
active patients must use an acceptable method of birth control.  Abstinence is an acceptable method of 
birth control see Section 4.2 for further details. 
2 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery 
to Grade 3 or until meeting the criteria for dose limiting toxicity. 
3 
If patients develop Grade 3 or greater thrombocytopenia then CBCs should be checked every 3 to 4 days 
until recovery per Section 6.1. 
4 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 
of either a PR or CR.  Subsequent scans may restart 2 cycles after the confirmatory scan. If the 
institutional investigator determines that the patient has progressed based on clinical or laboratory 
evidence, he/she may opt not to confirm this finding radiographically. 
4-A     Neurological exam also required for CNS patients 
4-B  Non- Hodgkin Lymphoma/ Histiocytosis patients are required to have PET scans within 2 weeks prior 
to start of therapy and should also be followed with PET scans if positive at diagnosis. Refer to Section 
12.8    
4-C     Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy prior to enrollment if the 
patient was enrolled with or has a history of having MIBG avid tumor. Otherwise, the patient must have 
both CT/MRI and bone scan prior to enrollment. For patients with neuroblastoma and measurable disease 
by CT or MRI, lesions should be measured and followed using the same modality (CT or MRI) in 
addition to MIBG or bone scan. For patients with neuroblastoma and evaluable disease by MIBG 
scintigraphy or bone scan, use the same modality (MIBG scintigraphy or bone scan) to image and follow 

 
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patients; CT/MRI are not required but may be performed as clinically indicated. Refer to Section 12.5.4 
and  Section 12.9. 
5 
Bone marrow aspirate and/or biopsy only required in patients suspected of having bone marrow 
metastasis on the basis of history, symptoms, laboratory evaluation or other clinical data. Should only 
be performed on patients with known bone marrow involvement at baseline.   
6 
Bone marrow aspirate and/or biopsy should be performed only when complete response or partial 
response is identified in target disease or when progression in bone marrow is suspected.  
7.  Patient diary (see Appendix III) should be reviewed after completion of each treatment cycle and 
uploaded into RAVE. The patient diary should be collected and reviewed weekly during Cycle 1. 
8. 
With consent two samples will be collected on this protocol (Cycle 5 Day 1; and for patients receiving 
≥ 5 cycles, at progression or end of protocol therapy) see Section 8.3 details of the ctDNA studies. 
Note that a ctDNA sample is scheduled to be obtained on the APEC 162SC screening protocol prior to 
the initiation of treatment on this subprotocol  
 
 
Radiology Studies 
 
Central Radiology Review for Response:   
Patients who respond (CR, PR) to therapy or have long term stable disease (SD) 
(≥ 6 cycles) on protocol therapy will be centrally reviewed.  The Operations center 
will notify the site when a patient has met the criteria for review. The tumor disease 
evaluations to be submitted for review include baseline (pre-study) evaluations as 
well as all end of cycle tumor disease evaluations which occurred while the patient 
was on the subprotocol therapy study. 
 
 
Technical Details of Submission:  
To ensure an adequate interpretation of FDG-PET and CT with contrast scans, 
scans transferred between the treating institutions and the Imaging and Radiation 
Oncology Core Group IROC RI (QARC) must be submitted in Digital Imaging 
and Communications in Medicine (DICOM) format. BMP ﬁles, JPG ﬁles, or hard 
copies (ﬁlms) are unacceptable for adequate interpretation of PET and CT with 
contrast scans. Imaging studies must be submitted electronically as outlined in the 
following paragraph. The images will be made available to study radiologists and 
nuclear medicine physicians for central review. 
 
Submission of Diagnostic Imaging data in DICOM format is required.  
Submission of the digital files and reports via TRIAD is preferred.  Instructions for 
TRIAD set up are below. 
 
Alternatively, the images and reports may be submitted via sFTP to IROC Rhode 
Island. Digital data submission instructions including instructions for obtaining a 
sFTP account, can be found at http://irocri.qarc.org. Follow the link labeled digital 
data.  Sites using the Dicommunicator software to submit imaging may continue 
to use that application. Corresponding Radiology reports may be submitted along 
with the electronic submission via TRIAD or sFTP or may be emailed to 
DataSubmission@QARC.org.   
 
Questions may be directed to DataSubmission@QARC.org or 401.753.7600. 
  
Digital RT Data Submission Using TRIAD (if TRIAD is available at your site): 
TRIAD is the American College of Radiology’s (ACR) image exchange 
application.  TRIAD provides sites participating in clinical trials a secure method 
to transmit DICOM and DICOM RT files and other digital objects, such as reports. 

 
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TRIAD de-identifies and validates the images as they are transferred. 
 
TRIAD Access Requirements: 
Site physics staff who will submit images through TRIAD will need to be 
registered with the Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management (IAM) account.  Please refer to 
CTEP Registration Procedures of the protocol for instructions on how to request a 
CTEP-IAM account. 
To submit images, the site TRIAD user must be on the site roster and be assigned 
the 'TRIAD site user' role on the CTSU roster.  Users should contact the site’s 
CTSU Administrator or Data Administrator to request assignment of the TRIAD 
site user role.   
 
TRIAD Installations: 
 
When a user applies for a CTEP-IAM account with the proper user role, he/she 
will need to have the TRIAD application installed on his/her workstation to be able 
to submit images. TRIAD installation documentation can be found by following 
this link https://triadinstall.acr.org/triadclient/   
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
 
If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
IROC Rhode Island (formerly QARC) will facilitate the central reviews. 
 
For FDG-PET imaging, the transferred imaging data should include uncorrected 
and attenuation-corrected PET projection data, as well as the reconstructed PET or 
PET/CT images used by the institution to achieve a response assessment. If low- 
dose CT was used for attenuation correction, the acquired CT images should also 
be submitted. The imaging data submitted for central review must allow the study 
to be reconstructed and displayed in transaxial, sagittal and coronal formats using 
standard reconstruction techniques. Reconstructed MPEG clips and similar types 
of reconstructions will not be accepted. CT and MRI images similarly should be 
submitted in a format that either includes properly reconstructed multi-planar 
viewing formats in soft tissue and bone windows, or includes the thin-section axial 
acquisition data from which multi-planar reconstructions can be re-created. 
 
Sites not able to submit imaging electronically may submit imaging via CD.   CD’s 
may be sent by courier to:  
 
Address for submission: IROC RI (QARC) 
Building B, Suite 201 
640 George Washington Highway Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax:     (401) 753-7601 
Web:    http://irocri.qarc.org 
 
 
Circulating Tumor DNA Study (optional) 

 
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Sampling Schedule   
An initial sample was previously requested at time of enrollment onto the pediatric 
MATCH screening protocol. Two additional samples will be collected into Streck 
Cell-Free DNA BCT tubes at the timepoints: 
 
 (1) Cycle 5 Day 1 
(2) At disease progression or end of protocol therapy (for patients receiving ≥ 5 
cycles of therapy only) 
  
Peripheral blood samples for circulating tumor DNA should be obtained as 
follows:  
• 
For patients ≥ 10 kg collect 20 mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg collect 10 mL (one tube)  
• 
For patients < 5 kg research samples will not be collected  
 
In all cases, blood draw volumes should strictly adhere to institutional limitations, 
taking other blood draws into consideration. However, if a reduction in volume is 
required, samples should be collected in 10 mL increments (ie. 0, 10, or 20 mL 
should be collected such that each Streck Cell-Free DNA BCT is completely 
filled). 
 
Established institutional guidelines should be followed for blood collection via 
vascular access devices. Heparin should be avoided in pre-collection flush 
procedures. If therapeutic heparin dosing contamination is a possibility, 
venipuncture is recommended as a first-choice collection method. If a Streck Cell-
Free DNA BCT tube immediately follows a heparin tube in the draw order, we 
recommend collecting an EDTA tube as a waste tube prior to collection in the 
Streck Cell-Free DNA BCT. 
 
For patients who do not have indwelling catheters, blood should be collected via 
venipuncture. To guard against backflow, observe the following precautions: 
• 
Keep patient’s arm in the downward position during the collection 
procedure. 
• 
Hold the tube with the stopper in the uppermost position so that the tube 
contents do not touch the stopper or the end of the needle during sample 
collection. 
• 
Release tourniquet once blood starts to flow in the tube, or within 2 
minutes of application. 
• 
Fill tube completely. 
• 
Remove tube from adapter and immediately mix by gentle inversion 8 to 
10 times. Inadequate or delayed mixing may result in inaccurate test 
results. 
 
 
Sample Processing 
Samples do not need to be processed at the collection site. 
 
 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 

 
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I.D (APEC1621I), and the date and time the sample was drawn.  Data should be 
recorded on the appropriate transmittal form found in RAVE. 
 
 
Sample Shipping Instructions 
Specimen should be shipped at room temperature to the BPC (address below). 
Upon arrival separation, extraction, and storage of plasma and cellular DNA will 
be performed. Samples should be shipped from Monday through Friday for 
Tuesday through Saturday delivery. If blood is collected over the weekend or on 
the day before a holiday, the sample should be stored in a refrigerator until shipped 
on the next business day.  Ship by FedEx Priority Overnight using the COG FedEx 
account. Blood samples should be shipped the same day as collection, ship blood 
for Saturday delivery if shipped on Friday. 
 
Ship specimens to the following address: 
 
 
 
Biopathology Center 
 
 
Nationwide Children’s Hospital 
 
 
Protocol APEC1621I– Peds MATCH* 
 
 
700 Children’s Drive, WA1340 
 
 
Columbus, OH 43205 
 
 
Phone: (614) 722-2865 
 
 
Fax: (614) 722-2897 
Email:BPCBank@nationwidechildrens.org 
 
*Packages must be labeled “Peds MATCH” in order to expedite processing at the 
BPC. 
 
Ship samples by FedEx Priority Overnight using a FedEx shipping label obtained 
through the COG FedEx account.  
 
 
9.0 
 AGENT INFORMATION 
 
 
Palbociclib (Ibrance®, PD-033299, 571190-30-2) 
NSC# 772256  
  
 
Structure and molecular weight  
Chemical name: 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2-
yl)amino]pyrido[2,3-d]pyrimidin-7-one 
 
Molecular Formula: C24H29N7O2  
 
 
 
 
Molecular weight: 447.54 Daltons 

 
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Supplied by: Palbociclib is supplied by Pfizer Inc. and distributed by a Division 
of Cancer Treatment and Diagnosis the Pharmaceutical Management Branch 
(DCTD), NCI. Do not use commercial supply. 
 
Formulation 
Palbociclib is supplied as 75 mg, 100 mg, and 125 mg hard shell gelatin capsules. 
Capsule excipients include microcrystalline cellulose, lactose monohydrate, 
sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate.  
Gelatin capsule colorants include red iron oxide, yellow iron oxide, and titanium 
dioxide.  White printing ink contains shellac, titanium dioxide, ammonium 
hydroxide, propylene glycol and simethicone. 
 
• 
75 mg capsules are opaque, hard gelatin capsules, size 2, with light orange 
cap and body, printed with white ink "Pfizer" on the cap, "PBC 75" on the 
body 
• 
100 mg capsules are opaque, hard gelatin capsules, size 1, with caramel 
cap and light orange body, printed with white ink "Pfizer" on the cap, 
"PBC 100" on the body on the body 
• 
125 mg capsules are opaque, hard gelatin capsules, size 0, with caramel 
cap and body, printed with white ink "Pfizer" on the cap, "PBC 125"  
 
Each bottle contains 21 capsules.  
 
 
Storage 
Store capsules at room temperature between 20 to 25ºC (68 to 77ºF); excursions 
permitted between 15 to 30 ºC (59 to 86 ºF) 
 
If a storage temperature excursion is identified, promptly return palbociclib to 
controlled room temperature and quarantine the supplies.  Provide a detailed report 
of the excursion (including documentation of temperature monitoring and duration 
of the excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability.   
 
Stability 
Refer to the package label for expiration.  
 
 
Administration 

 
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See Treatment and Dose Modification sections of the protocol.  
Palbociclib capsules should be swallowed whole and taken with food. Do not crush, 
chew or open capsules prior to swallowing. If the patient vomits or misses a dose, an 
additional dose should not be taken. The next prescribed dose should be taken at the 
usual time. 
 
 
Potential Drug Interactions 
In vivo data indicate that CYP3A4 is important for palbociclib metabolism and 
clearance in humans. For this reason, avoid concomitant administration of strong and 
moderate CYP 3A4 inducers and inhibitors (see Appendix II for list of agents).   
 
In vitro data indicated that palbociclib has a low potential to inhibit the activities of 
drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), 
organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2 and 
organic anion transporting polypeptide (OATP)1B1, OATP1B3 at clinically relevant 
concentrations. Based on in vitro data, P-gp and BCRP mediated transport are 
unlikely to affect the extent of oral absorption of palbociclib at therapeutic doses. 40 
 
Palbociclib is a weak time-dependent inhibitor of CYP3A4 in humans. The use of 
sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow therapeutic 
range should be avoided for the duration of the study, if reasonable alternatives 
exist (Appendix II).  
 
 
 
Palbociclib Toxicities 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). Refer 
to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applicatio
ns/docs/aeguidelines.pdf for further clarification. Frequency is provided based on 
1751 patients. Below is the CAEPR for Palbociclib (PD-0332991). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
Version 2.4, September 13, 20191 
 
Adverse Events with Possible 
Relationship to Palbociclib (PD-0332991) 
(CTCAE 5.0 Term) 
[n= 1751] 
  Specific Protocol Exceptions to 
Expedited Reporting  
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  

 
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Adverse Events with Possible 
Relationship to Palbociclib (PD-0332991) 
(CTCAE 5.0 Term) 
[n= 1751] 
  Specific Protocol Exceptions to 
Expedited Reporting  
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Anemia 
 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Dry eye 
 
  
 
Watering eyes 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Constipation 
 
 Constipation (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
  
INFECTIONS AND INFESTATIONS 
  
Infection2 
 
 
 Infection2 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
  
 
Aspartate 
aminotransferase 
increased 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 2) 
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
White blood cell decreased 
 
 
 White blood cell decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
  
 
Headache3 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Epistaxis 
 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
  
 
Skin and subcutaneous tissue 
disorders - Other (rash)4 
 
  
 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. 
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2 Infection includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
3Headache has been observed in trials using Palbociclib (PD-0332991) in combination with fulvestrant. 
 

 
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4 Rash includes rash, rash maculo-papular, erythema, erythematous rash, erysipelas, rash pruritic, rash papular, 
generalized rash, exanthema, allergic dermatitis, dermatitis acneiform, and dermatitis. 
 
5 Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory neuropathy under the 
NERVOUS SYSTEM DISORDERS SOC.. 
Adverse events reported on palbociclib (PD-0332991) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that palbociclib (PD-0332991) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Blood and lymphatic system 
disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Cardiac disorders - Other (paroxysmal atrial fibrillation 
with rapid ventricular response); Palpitations; Pericarditis; Sinus bradycardia; Supraventricular tachycardia 
EYE DISORDERS - Cataract; Eye disorders - Other (retinal hemorrhage) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Ascites; Colitis; Colonic 
perforation; Dry mouth; Dyspepsia; Dysphagia; Esophageal stenosis; Flatulence; Gastric hemorrhage; Gastrointestinal 
disorders - Other (gastrointestinal hemorrhage); Intra-abdominal hemorrhage; Lower gastrointestinal hemorrhage; 
Small intestinal obstruction; Small intestinal perforation; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema limbs; 
Localized edema; Malaise; Non-cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (bile duct obstruction); 
Hepatobiliary disorders - Other (jaundice) 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; Creatinine 
increased; Ejection fraction decreased; GGT increased; INR increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; Hyperkalemia; 
Hypermagnesemia; 
Hyperuricemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypokalemia; 
Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Flank pain; 
Generalized muscle weakness; Muscle cramp; Musculoskeletal and connective tissue disorder - Other (osteomyelitis); 
Myalgia; Neck pain; Osteonecrosis; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL. CYSTS AND POLYPS) - Treatment 
related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Dysphasia; Intracranial hemorrhage; Nervous system 
disorders - Other (peripheral neuropathy)5; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Psychiatric disorders - Other (altered mental status) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Hypoxia; Oropharyngeal 
pain; Pleural effusion; Postnasal drip; Pulmonary edema; Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Pruritus 
VASCULAR DISORDERS - Hypertension; Hypotension 
 
 
Note: Palbociclib (PD-0332991) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously associated 
with either agent. 
 
 
 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.    The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 

 
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Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there are 
several participating investigators at one institution, CTEP-supplied investigational agents 
for the study should be ordered under the name of one lead participating investigator at that 
institution. 
                           
Note: No starter supplies will be provided. Drug orders of palbociclib should be 
placed with CTEP after enrollment and treatment assignment to APEC1621I with 
consideration for timing of processing and shipping to ensure receipt of drug supply 
prior to start of protocol therapy. If expedited shipment is required, sites should provide 
an express courier account through the Online Agent Order Processing (OAOP) 
application. Provide the patient ID number in the comment box when submitting an order 
request. 
 
 
Clinical Drug Request and Investigator Brochure Availability 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. The current versions of the IBs for the agents will also be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a “current” 
password and active person registration status. For questions about drug orders, transfers, 
returns, or accountability call or email PMB anytime. Refer to the PMB’s website for 
specific policies and guidelines related to agent management. Questions about IB access 
may be directed to the PMB IB coordinator via email. 
 
 
 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
9.4.1.1 Useful Links and Contacts  
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
 
 
http://ctep.cancer.gov/branches/pmb/agent_management.htm    
• PMB Online Agent Order Processing (OAOP) application:  
 
 
https://ctepcore.nci.nih.gov/OAOP  
• CTEP Identity and Access Management (IAM) account:  
   
  https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: 
 
ctepreghelp@ctep.nci.nih.gov  
• PMB email: PMBAfterHours@mail.nih.gov  
• PMB phone and hours of service: (240) 276-6575  
Monday through Friday between 8:30 am and 4:30 pm (ET) 
• PMB IB Coordinator: IBcoordinator@mail.nih.gov 
• Registration and Credential Repository (RCR): 
https://ctepcore.nci.nih.gov/rcr/  
 

 
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10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6). 
c) 
Refusal of protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of 26 cycles of therapy. 
f) 
Physician determines it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of protocol therapy (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
j) 
Patient did not receive protocol treatment after study enrollment 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent from the APEC1621SC screening protocol. Patients who are removed from 
protocol therapy in subsequent cycles should have the necessary observations to 
ensure adequate clinical care.  
 
 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
Patients who are off subprotocol therapy will continue to be followed on the APEC1621SC 
screening protocol. Follow-up data submission will occur until one of the APEC1621SC 
Off Study Criteria is met (See Section 10 of APEC1621SC for details). Ongoing adverse 
events, or adverse events that emerge after the patient is removed from protocol therapy, 
but within 30 days of the last dose of investigational agent, must be followed and reported 
via RAVE and CTEP-AERS (if applicable).  Follow-up data will be required until off study 
criteria are met unless consent is withdrawn or the patient dies or is lost to follow-up. 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
 
Sample Size and Study Duration 
APEC1621I will require a minimum of 20 evaluable patients and a maximum of 49 
patients, allowing for 15% inevaluability. Assuming an enrollment rate of 4-6 biomarker 
positive patients per year, this subprotocol is expected to be completed within 8-12 years. 
 
 
Dosing Considerations  
A pediatric MTD/RP2D has been established for palbociclib; therefore patients will be 
treated at that dose38. Please see section 5.1 for a specific discussion of the dosing of 
palbociclib to be used in this study.   
 
 
Study Design 

 
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The primary cohort defined below will employ single stage A’Hern designs of N=20 and 
N=10 respectively. The agent will be deemed worthy of further study in the relevant subset 
of patients (i.e. biomarker positive in any histology, biomarker positive in a particular 
histology, etc) if the decision rule is met. Operating characteristics are shown below. 
 
Cohort 
N 
Decision Rule 
Alpha Power 
Primary biomarker positive 20 ≥ 3 responses 
10% 
90% 
 
Histology-specific biomarker positive expansion cohorts will, by definition, be deemed 
worthy of further study, since they will have at least 3 responses. The table below shows 
90% confidence intervals (Wilson method) for a range of observable response rates. 
 
Cohort Size Observed Response Rate 90% Confidence Interval 
10 
30% 
13% - 56% 
10 
40% 
19% - 65% 
10 
50% 
27% - 73% 
 
 Primary Cohort:  
APEC1621I will evaluate a primary cohort of 20 mutation-matched (“biomarker 
positive”) evaluable patients of any histology for the primary study aim of 
determining the objective response rate  (CR/PR according to the response criteria  
in Section 12.3)  to the agent. Using an A’Hern design41 with alpha=10%, a sample 
of N=20 will provide 90% power to detect an improvement in response rate from 
5%, if the treatment is ineffective, to 25% if the targeted therapy is sufficiently 
effective to warrant further study. If there are at least 3 responses out of 20 in the 
primary cohort, the biomarker/therapy match will be deemed a success.  
 
 Histology-Specific Biomarker Positive Expansion Cohorts:  
If ≥ 3 patients in the primary cohort with the same histology show signs of 
objective response (CR/PR according to the response criteria  in Section 12.3), a 
histology-specific biomarker positive expansion cohort will open after the primary 
cohort is completed to up to 7 evaluable patients for a total sample size of 10 
evaluable biomarker positive patients with that histology. This will allow us to 
estimate more precisely the activity in biomarker positive patients of that 
histology. See Appendix VII for a list of target tumor histologies.  
We will open up to 3 such expansion cohorts for biomarker positive patients (i.e., 
if 3 histologies have ≥ 3 responses, we will open a total of 3 expansion cohorts as 
described above). Note that this can only happen if the response rate in the primary 
cohort is at least 45% (9/20) and there cannot be more than 21 additional evaluable 
patients in total for these expansion cohorts. 
 
 
 
Methods of Analysis 
Response criteria are described in Section 12. A responder is defined as a patient who 
achieves a best response of PR or CR on the study. Response rates will be calculated as the 
percent of evaluable patients who are responders, and confidence intervals will be 
constructed using the Wilson score interval method.42 Decision making for A’Hern design 
cohorts will follow rules described above. 
 
Toxicity tables will be constructed to summarize the observed incidence by type of toxicity 
and grade. A patient will be counted only once for a given toxicity for the worst grade of 

 
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that toxicity reported for that patient. Toxicity information recorded will include the type, 
severity, time of onset, time of resolution, and the probable association with the study 
regimen.   
 
 
Evaluability for Response 
Any eligible patient who is enrolled and receives at least one dose of protocol therapy will 
be considered evaluable for response. Any patient who receives non-protocol anti-cancer 
therapy during the response evaluation period will be considered a non-responder for the 
purposes of the statistical rule, unless they show an objective response prior to receiving 
the non-protocol anti-cancer therapy (in which case they will be considered a responder). 
Patients who demonstrate a complete or partial response confirmed by central review will 
be considered to have experienced a response. When opening expansion cohorts, the 
evaluation period for determination of best response will be 6 treatment cycles. All other 
patients will be considered non-responders. Patients who are not evaluable for response 
evaluation may be replaced for the purposes of the statistical rule. All patients considered 
to have a response (CR or PR) must have imaging studies reviewed centrally at the COG. 
Centers will be notified by the COG about requests for scans of patients with stable disease. 
Preliminary assessment of activity using institutionally provided tumor measurements will 
be entered into CDUS quarterly. The central review by COG will be provided as the final 
reviewed assessment of response when such becomes available. 
 
Evaluability for Toxicity 
All patients who receive at least one dose of protocol therapy will be considered in the 
evaluation of toxicity. 
 
Progression free survival (PFS) 
Progression free survival will be defined as time from the initiation of protocol treatment 
to the occurrence of any of the following events: disease progression or disease 
recurrence or death from any cause. All patients surviving at the time of analyses without 
events will be censored at their last follow-up date. 
 
PFS along with the confidence intervals will be estimated using the Kaplan-Meier method. 
Patients with local calls of disease progression (i.e. calls made by the treating institution), 
will be counted as having had an event, even if the central review does not declare 
progression. We will also report PFS based on central radiology review as a secondary 
analysis, if adequate number of disagreements in progressions exist between the treating 
institutions and the central radiology review to make such an analysis meaningful.     
 
 
 
Correlative Studies 
A descriptive analysis of pharmacokinetic (PK) parameters will be performed to define 
systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK 
parameters will be summarized with simple summary statistics, including means, medians, 
ranges, and standard deviations (if numbers and distribution permit).   
 
A descriptive analysis of the exploratory aims described in Section 1.3 will be performed 
and will be summarized with simple summary statistics. All of these analyses will be 
descriptive in nature. 
 
 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
 

 
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Racial category 
Ethnicity 
Total 
Not Hispanic 
or Latino 
Hispanic or 
Latino 
Female Male Female Male 
American Indian/Alaska Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
3 
5 
0 
0 
8 
White 
12 
20 
4 
2 
38 
More than one race 
1 
0 
0 
0 
1 
Total 
17 
26 
4 
2 
49 
 
This distribution was derived from the demographic data for patients enrolled on recent COG 
Phase 2 trials. 
 
 
12.0 
EVALUATION CRITERIA 
 
 
Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
The descriptions and grading scales found in the current version of the NCI Common 
Terminology Criteria for Adverse Events v.5.0 (CTCAE) will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the current 
CTCAEv5.0.  A copy of the CTCAEv5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.). 
 
 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of subprotocol 
treatment to time of progression or death, whichever occurs first. 
 
Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g., when multiple lesions 
show opposite responses, the progressive disease takes precedence. 
 
 
Response Criteria for Patients with Solid Tumors  
See the table in Section 8.0 for the schedule of tumor evaluations. In addition to the 
scheduled scans, a confirmatory scan should be obtained on the next consecutive cycle 
following initial documentation of objective response. 
 
As outlined, patients will be assigned to one of the following categories for assessment of 
response:  a) solid tumor (non-CNS) and measurable disease (Section 12.4); b) 
neuroblastoma with MIBG positive lesions (Section 12.5); c) CNS tumor (Section 12.7); 
and d) lymphoma/hystiocytosis (Section 12.8). Note: Neuroblastoma patients who do not 
have MIBG positive lesions should be assessed for response as solid tumor patients with 
measurable disease. 
 
Response and progression will be evaluated in this study using the revised Response 

 
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Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].  Key points are that 5 target lesions are identified and that changes in the largest 
diameter (unidimensional measurement) of the tumor lesions but the shortest diameter of 
malignant lymph nodes are used in the RECIST v 1.1 criteria. 
 
 Definitions 
 
12.3.1.1 Evaluable for objective response:  
Eligible patients who receive at least one dose of protocol therapy will 
be considered evaluable for response. Evaluable patients who 
demonstrate a complete or partial response confirmed by central review 
before receiving non-protocol anti-cancer therapy will be considered a 
responder. All other evaluable patients will be considered non-
responders 
 
12.3.1.2 Evaluable Non-Target Disease Response: 
  
Eligible patients who have lesions present at baseline that are evaluable 
but do not meet the definitions of measurable disease and have received 
at least one dose of protocol therapy will be considered evaluable for 
non-target disease response. The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
 
 Disease Parameters 
 
12.3.2.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 
mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable. If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
12.3.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
12.3.2.3 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm short axis), are considered non-measurable 
disease. 
 
Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 

 
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simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
12.3.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion that can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
 
12.3.2.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
12.3.3.1 Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and  10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
12.3.3.2 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable.  
 

 
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12.3.3.3 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 
12.3.3.4 PET-CT:  At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
12.3.3.5 Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.  
 
12.3.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.3.3.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 

 
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 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
For patients with a positive PET scan at diagnosis, PET can be used to 
follow response in addition to a CT scan using the International Pediatric 
non-Hodgkin Lymphoma Response Criteria.43 
 
 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 
is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 

 
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short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
 Overall Response Assessment 
 
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 28 days Confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥ 28 days Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once ≥ 
28 days from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 

 
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Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Table 3: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.9  from a sequence of overall response assessments. 
 
 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive 
lesions 
Progressive disease: Development of new MIBG positive lesions 
 
 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 

 
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The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 
 
 
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
 
 Overall Response Assessment 
 
Table 4: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease 
Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly 
identified lesion by CT/MRI that occurs during therapy would be considered 
progressive disease. 

 
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MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.9. 
 
 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
 Bone Marrow Involvement  
Note: patients with bone marrow as the ONLY site of disease are not eligible for 
this study. Response criteria in this section are intended to be used when assessing 
marrow involvement as a component of overall response.  
 
Histologic analysis at the local institution of marrow tumor cell involvement is 
required for patients with a history of marrow involvement. Marrow aspirate and 
biopsy should be evaluated at baseline and every 2 cycles thereafter. Note: If 
progressive disease is documented by RECIST criteria using tumor measurements 
or by MIBG scan, then a repeat BM is not needed to confirm PD.  
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 
morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 
tumor is detected in 2 consecutive bone marrow biopsies 
or aspirations done at least 21 days apart. 
 

 
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Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.9. 
 
 
Response Criteria for Patients with CNS Tumors 
 
 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 
 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 
• 
Complete Response (CR): Disappearance of all target lesions. Off all steroids 
with stable or improving neurologic examination. 
 
• 
Partial response (PR): ≥ 50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements; on a stable or decreasing dose of steroids with 
a stable or improving neurologic examination. 
 
• 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of 
the two perpendicular diameters of all target lesions to qualify for PR, nor 

 
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sufficient increase in a single target lesion to qualify for PD; on a stable or 
decreasing dose of steroids with a stable or improving neurologic examination. 
 
• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
 
Increasing doses of corticosteroids required to maintain stable neurological status 
should be strongly considered as a sign of clinical progression unless in the context 
of recent wean or transient neurologic change due e.g. to radiation effects. 
 
 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
 Overall Response Assessment 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 
Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.9 from a sequence of overall response assessments. 
 

 
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Response Criteria for Patients with Lymphoma/Histiocytosis 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Pediatric non-Hodgkin 
Lymphoma Criteria43, with modification from the Lugano classification.44 
 
 Disease Parameters 
 
1. 
Measurable disease: A measurable node must have an LDi (longest diameter) 
greater than 1.5 cm. A measurable extranodal lesion should have an LDi greater 
than 1.0 cm. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
2. 
Non-measured disease: All other lesions (including nodal, extranodal, and 
assessable disease) should be followed as nonmeasured disease (e.g., cutaneous, 
GI, bone, spleen, liver, kidneys, pleural or pericardial effusions, ascites).   
 
3. 
Target lesions: For patients staged with CT, up to six of the largest target nodes, 
nodal masses, or other lymphomatous lesions that are measurable in two diameters 
(longest diameter [LDi] and shortest diameter) should be identified from different 
body regions representative of the patient’s overall disease burden and include 
mediastinal and retroperitoneal disease, if involved. 
 
 Evaluation of Measurable Disease 
 
Complete Response (CR) 
Disappearance of all disease. CT or MRI should be free of residual mass or 
evidence of new disease. FDG-PET should be negative. 
 
Complete Response Unconfirmed (CRu) 
Residual mass is negative by FDG-PET; no new lesions by imaging examination; 
no new and/or progressive disease elsewhere 
 
Partial Response (PR) 
50% decrease in SPD (the sum of the products of the largest diameter and the 
perpendicular diameter for a tumor mass) on CT or MRI; FDG-PET may be 
positive (Deauville score or 4 or 5 with reduced lesional uptake compared with 
baseline); no new and/or PD; morphologic evidence of disease may be present in 
BM if present at diagnosis; however, there should be 50% reduction in percentage 
of lymphoma cells. 
 
No Response (Stable Disease) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
Progressive disease 
For those with > 25% increase in SPD on CT or MRI, Deauville score 4 or 5 on 
FDG-PET with increase in lesional uptake from baseline, or development of new 
morphologic evidence of disease in BM  
 
 Evaluation of Non-measured Lesions (CT-based response, PET/CT based 

 
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response not applicable)44 
 
Complete Response (CR): 
Absent non-measured lesions.  
 
Partial response (PR): 
Absent/normal, regressed, lesions, but no increase. 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): New 
or 
clear 
progression 
of 
preexisting 
non-measured lesions. 
 
 Evaluation of organ enlargement44  
 
Complete Response (CR): 
Regress to normal  
 
Partial response (PR): 
Spleen must have regressed by >50% in length 
beyond normal 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): In the setting of splenomegaly, the splenic length 
must increase by 50% of the extent of its prior 
increase beyond baseline. If no prior splenomegaly, 
must increase by at least 2 cm from baseline.  
 
New or recurrent splenomegaly 
 
 
Best Response 
Two objective status determinations of disease status, obtained on two consecutive 
determinations, separated by at least a 3-week time period, are required to determine the 
patient’s overall best response. Two objective status determinations of CR before 
progression are required for best response of CR. Two determinations of PR or better 
before progression, but not qualifying for a CR, are required for a best response of PR. 
Two determinations of stable/no response or better before progression, but not qualifying 
as CR or PR, are required for a best response of stable/no response; if the first objective 
status is unknown, only one such determination is required. Patients with an objective 
status of progression on or before the second evaluations (the first evaluation is the first 
radiographic evaluation after treatment has been administered) will have a best response of 
progressive disease. Best response is unknown if the patient does not qualify for a best 
response of progressive disease and if all objective statuses after the first determination and 
before progression are unknown. 
 
 
 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
Table 5.  Sequences of overall response assessments with corresponding best 

 
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response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
 Duration of Response 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the Case Report Forms 
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
 
 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
 

 
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Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
 Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair 
have the primary responsibility for AE identification, documentation, grading, and 
assignment of attribution to the investigational agent/intervention. It is the 
responsibility of the treating physician to supply the medical documentation 
needed to support the expedited AE reports in a timely manner.  
 
Any medical documentation supporting an expedited report (eg, H & P, 
admission and/or notes, consultations, ECG results, etc.) MUST be faxed 
within 48-72 hours to the NCI. NOTE: English is required for supporting 
documentation submitted to the numbers listed below in order for the NCI to 
meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents 
supplied under a CTEP IND to: (301) 897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax# 
(310) 640-9193; email: COGAERS@childrensoncologygroup.org; Attention: 
COG AERS Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
 CTEP-AERS Expedited Reporting Methods  
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page  
https://ctepcore.nci.nih.gov/ctepaers/pages/task. 
 

 
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Send supporting documentation to the NCI by fax (fax# 301-640-9193) and by 
email to COGCAdEERS@childrensoncologygroup.org ,  
the 
APEC1621I 
COG 
Study 
Assigned 
Research 
Coordinator, 
and 
COGAERS@childrensoncologygroup.org; Attention: COG AERS Coordinator.  
ALWAYS include the ticket number on all faxed and emailed documents. 
 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the current version 5.0 of the NCI CTCAE.  
All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Step 2:  Grade the adverse event using the NCI CTCAEv5.0. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
• 
Any medical event equivalent to CTCAEv5.0 grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported regardless 
of attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
• 
As referenced in the CTEP Adverse Events Reporting Requirements, an AE that 
resolves and then recurs during a subsequent cycle does not require CTEP-AERS 
reporting unless (1) the Grade increases; or (2) hospitalization is associated with the 
recurring AE. 
 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at http://ctep.cancer.gov (telephone CTEP at: 301-897-7497 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable). Once internet connectivity is restored, a 24-hour notification 
phoned in must be entered electronically into CTEP-AERS by the original submitter at 
the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 

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

 
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Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements: 
 
• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), 
does not require expedited reporting, unless it is associated with hospitalization. 
Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
• Grade 1 and 2 adverse events listed in the table below do not require expedited reporting 
via CTEP-AERS, unless it is associated with hospitalization. 
Category 
Adverse Events 
EYE DISORDERS 
Dry Eye 
EYE DISORDERS 
Watering Eyes 
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS 
Fever 
NERVOUS SYSTEM DISORDERS  
Dysgeusia  
NERVOUS SYSTEM DISORDERS 
Headache 
RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS 
Epistaxis 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Dry Skin  
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Skin and subcutaneous 
tissue disorders - Other 
(rash) 
 
• See also the Specific Protocol Exceptions to Expedited Reporting (SPEER) in Section 9.1.8 
of the protocol.   
 
 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG case report 
forms and do not alter the guidelines for CTEP-AERS reporting. 
 
 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
 If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
 The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than or equal to Grade 1, whichever level is higher (note that the 
resolution date may therefore be different from the date at which the grade of the 
AE decreased from its highest grade).  If the AE does not return to baseline the 

 
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resolution date should be recorded as "ongoing."   
 
 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
 
Other Recipients of Adverse Event Reports 
 
 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the CRF 
packet (See Section 14.1). 
 
 Adverse events determined to be reportable must also be reported according to the 
local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
 
Specific Examples for Expedited Reporting 
 
 Reportable Categories of Death 
• 
Death attributable to a CTCAEv5.0 term.  
• Death Neonatal: “Newborn deaths occurring during the first 28 days after 
birth” 
• Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be attributed 
to a CTCAEv5.0 term associated with Grade 5.  
• Death NOS: A cessation of life that cannot be attributed to a CTCAEv5.0 term 
associated with Grade 5.  
• Death due to progressive disease should be reported as Grade 5 “Disease 
progression” under the system organ class (SOC) of “General disorders and 
administration site conditions.” Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
• Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 
hours.  
 
• Any death that occurs more than 30 days after the last dose of treatment with 
an investigational agent which can be attributed (possibly, probably, or 
definitely) to the agent and is not clearly due to progressive disease must be 
reported via CTEP-AERS per the timelines outlined in the table above. 
 
 Reporting Secondary Malignancy 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, 
radiation 
or 

 
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chemotherapy). A secondary malignancy is not considered a metastasis of the 
initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute 
myelocytic leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy).  Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
 Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Neonatal 
loss”, 
the 
Pregnancy 
Information 
Form, 
available 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to (301) 230-0159. The potential risk of exposure of the fetus 
to the investigational agent should be documented in the “Description of Event” 
section of the CTEP-AERS report. 
 
Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the fetus to 
agents that may be teratogenic. For this reason, pregnancy needs to be reported in 
an expedited manner via CTEP-AERS as Grade 3 “Pregnancy, puerperium and 
perinatal conditions - Other (pregnancy)” under the “Pregnancy, puerperium 
and perinatal conditions” SOC. 
 
• 
Pregnancy needs to be followed until the outcome of the pregnancy is 
known at intervals deemed appropriate by her physicians. The “Pregnancy 
Information Form” should be used for all necessary follow-ups. This form 
is available at http://ctep.cancer.gov/protocolDevelopment/electronic
_applications/docs/PregnancyReportForm.pdf. If the baby is born with a 
birth defect or anomaly, then a second CTEP-AERS report is required. 
 
Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
 
Any pregnancy loss needs to be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 

 
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Death Neonatal 
Neonatal death, defined in CTCAEv5.0 as “Newborn deaths occurring during the 
first 28 days after birth” that is felt by the investigator to be at least possibly due 
to the investigational agent/intervention, should be reported expeditiously, as 
Grade 4 “Death Neonatal” under the system organ class (SOC) of “General 
disorders and administration site conditions.” When the death is the result of a 
patient pregnancy or pregnancy in partners of men on study. Do NOT report 
a neonatal death resulting from a patient pregnancy or pregnancy in partners of 
men on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event 
as a patient death.  
 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the case report form (CRF) 
packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, July 
31 and October 31.  This is not a responsibility of institutions participating in this trial. 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.   
 
 
CRADA/CTA/CSA 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 

 
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(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
4. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
5. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order 
as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected , used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 

 
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with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP for immediate delivery to Collaborator(s) for advisory review and comment 
prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and 
other media presentations must also be forwarded to CTEP prior to release. Copies 
of any manuscript, abstract and/or press release/ media presentation should be sent 
to: 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the developmental therapy 
scientific committee; and a member from the NCI. The DSMC meets at least every 
6 months to review current study results, as well as data available to the DSMC 
from other related studies. Approximately 6 weeks before each meeting of the 
Phase 1 and 2 DSMC, study chairs will be responsible for working with the study 
statistician to prepare study reports for review by the DSMC. The DSMC will 
provide recommendations to the COG Developmental Therapeutics Chair and the 
Group Chair for each study reviewed to change the study or to continue the study 
unchanged. Data and Safety Committee reports for institutional review boards can 
be prepared using the public data monitoring report as posted on the COG Web 
site. 
 
 Monitoring by the Study Chair and MATCH Leadership  
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the 
MATCH Chair, Vice Chair and Statistician on a weekly conference call. 

 
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30. 
Finn RS, Crown JP, Lang I, et al: The cyclin-dependent kinase 4/6 inhibitor palbociclib in 
combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-
positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 
study. Lancet Oncol 16:25-35, 2015 
31. 
Turner NC, Ro J, Andre F, et al: Palbociclib in Hormone-Receptor-Positive Advanced Breast 
Cancer. N Engl J Med 373:209-19, 2015 
32. 
Dickson MA, Tap WD, Keohan ML, et al: Phase II trial of the CDK4 inhibitor PD0332991 in 
patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin 
Oncol 31:2024-8, 2013 
33. 
Schwartz GK, LoRusso PM, Dickson MA, et al: Phase I study of PD 0332991, a cyclin-dependent 
kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer 104:1862-8, 2011 
34. 
Slamon DJ, Hurvitz SA, Applebaum S, et al: Phase I study of PD 0332991, cyclin-D kinase (CDK) 
4/6 inhibitor in combination with letrozole for first-line treatment of patients with ER-positive, 
HER2-negative breast cancer. Journal of Clinical Oncology 28:3060-3060, 2010 
35. 
Littman SJ, Brus C, Burkart A: A phase II study of palbociclib (PD-0332991) in adult patients with 
advanced hepatocellular carcinoma. Journal of Clinical Oncology 33:277-277, 2015 
36. 
Hu W, Sung T, Jessen BA, et al: Mechanistic Investigation of Bone Marrow Suppression 
Associated with Palbociclib and its Differentiation from Cytotoxic Chemotherapies. Clinical 
Cancer Research 22:2000-2008, 2016 
37. 
Turner NC, Ro J, Andre F, et al: PALOMA3: A double-blind, phase III trial of fulvestrant with or 
without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-
negative metastatic breast cancer that progressed on prior endocrine therapy. Journal of Clinical 
Oncology 33:LBA502-LBA502, 2015 
38. 
Gururangan S, Becher O, Leary S, et al: Phase I Trial of Palbociclib, a CDK4/6 Inhibitor in Children 
with Retinoblastoma Protein (RB1) + Recurrent Central Nervous System (CNS) Tumors (PBTC 
042). Neuro Oncol 18(Suppl 3): iii28, 2016 
39. 
Geoerger B, Bourdeaut F, Dubois SG, et al: Phase I study of LEE011 (CDK4/6 inhibitor) in patients 
with malignant rhabdoid tumors, neuroblastoma, and cyclin-D-CDK4/6 pathway-activated tumors. 
Ann. Oncol 25 (Supplement 4), 2014 
40. 
Ibrance® (palbocicib) [package insert] Pfizer Inc., New York, NY; February 2016  

 
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41. 
A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 20:859-66, 2001 
42. 
Agresti A, Coull BA: Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician 52:119-126, 1998 
43. 
Sandlund JT, Guillerman RP, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol 33:2106-11, 2015 
44. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32:3059-68, 2014 
 
 

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

 
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APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
 
This is not an inclusive list. Because the lists of these agents are constantly changing, it is important to 
regularly consult frequently updated medical references. 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers 
Moderate 
Inducers 
abemaciclib 
acalabrutinib5 
alfentanil4,5  
alprazolam5 
amiodarone4 
amlodipine 
aprepitant/fosaprepitant 
atorvastatin 
avanafil5 
axitinib 
bortezomib 
bosutinib5 
brexpiprazole 
brigatinib 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
colchicine5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
ebastine5 
eletriptan5 
eliglustat5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
felodipine5 
fentanyl4 
atazanavir 
boceprevir 
clarithromycin 
ceritinib 
cobicistat 
danoprevir/ritonavir 
darunavir 
delavirdine 
elvitegravir/ritonavir 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir/ritonavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
paritaprevir/ritonavir/ 
ombitasvir +/- dasabuvir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
tipranavir/ritonavir 
tucatinib 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
duvelisib 
erythromycin 
fedratinib 
fluconazole 
fosamprenavir 
fosnetupitant 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
lefamulin 
letermovir 
mifepristone 
netupitant 
nilotinib 
ribociclib 
verapamil 
apalutamide 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
lumacaftor/ 
ivacaftor 
mitotane 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
cenobamate 
dabrafenib 
efavirenz 
eslicarbazepine 
etravirine 
lorlatinib 
modafinil 
nafcillin 
pexidartinib 
rifabutin 
rifapentin 
 
 
 

 
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gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
lomitapide5 
lorlatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
naloxegol5 
nefazodone 
nilotinib 
nisoldipine5 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
pimozide5 
quetiapine5 
quinidine4  
regorafenib 
rilpivirine5 
rivaroxaban5 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
tadalafil5 
telaprevir 
temsirolimus 

 
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teniposide 
tetracycline 
ticagrelor5 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 4.2.2 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors) 

 
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APPENDIX III:  MEDICATION DIARY FOR PALBOCICLIB 
 
COG Patient ID:___________   Acc#_________________ 
 
 
 
 
  
 
Institution :________________________________  
Please do not write patient names on this form. 
 
Complete each day with the time and dose given for palbociclib. Palbociclib will be given by mouth once daily with food on 
days 1-21, then rest for 7 days. Take at approximately the same time each day. If a  dose is accidentally skipped leave that day 
blank. Make note of other drugs and supplements taken under the Comments section below. Palbociclib capsules should not 
be opened or crushed but should be swallowed whole. If capsule is broken and the powder of the capsules gets on skin, wash 
the exposed area with as much water as necessary. If the patient vomits or misses a dose, an additional dose should not be 
taken. The next prescribed dose should be taken at the usual time. Inform your study doctor or nurse if that occurs. Add the 
dates to the calendar below and return the completed diary to your institution after each treatment cycle.  
 
EXAMPLE 
 
 
Number of Palbociclib 
capsules 
Comments 
 
 
Date 
Time 
75 mg 
100 mg 
125 mg 
 
Day 1 
1/15/14 
8:30 AM 
1 
0 
0 
He felt nauseated an hour after taking 
the drug but did not vomit. 
    
 
Cycle #: _____    Start Date: |__/__|__/__|__/__|       End Date: |__/__|__/__|__/__|              Dose Level:            mg/m2 
WEEK 1 
Date 
Time 
# of palbociclib capsules prescribed 
to take 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
75 mg 
100 mg 
125 mg 
 
 
 
 
 
# of palbociclib capsules taken  
75 mg 
100 mg 
125 mg 
Day 1 
 
 
AM /  PM 
 
 
 
 
Day 2 
 
 
AM/  PM 
 
 
 
 
Day 3 
 
 
AM/  PM 
 
 
 
 
Day 4 
 
 
AM/  PM 
 
 
 
 
Day 5 
 
 
AM/  PM 
 
 
 
 
Day 6 
 
 
AM/  PM 
 
 
 
 
Day 7 
 
 
AM/  PM 
 
 
 
 

 
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Cycle #: _____    Start Date: |__/__|__/__|__/__|       End Date: |__/__|__/__|__/__|              Dose Level:            mg/m2 
WEEK 2 
Date 
Time 
# of palbociclib capsules prescribed 
to take 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
75 mg 
100 mg 
125 mg 
 
 
 
 
# of palbociclib capsules taken 
75 mg 
100 mg 
125 mg 
Day 8 
 
 
AM /  PM 
 
 
 
 
Day 9 
 
 
AM/  PM 
 
 
 
 
Day 10 
 
 
AM/  PM 
 
 
 
 
Day 11 
 
 
AM/  PM 
 
 
 
 
Day 12 
 
 
AM/  PM 
 
 
 
 
Day 13 
 
 
AM/  PM 
 
 
 
 
Day 14 
 
 
AM/  PM 
 
 
 
 
WEEK 3 
Date 
Time 
# of palbociclib capsules prescribed 
to take 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
75 mg 
100 mg 
125 mg 
 
 
 
 
# of palbociclib capsules taken 
75 mg 
100 mg 
125 mg 
Day 15 
 
 
AM /  PM 
 
 
 
 
Day 16 
 
 
AM/  PM 
 
 
 
 
Day 17 
 
 
AM/  PM 
 
 
 
 
Day 18 
 
 
AM/  PM 
 
 
 
 
Day 19 
 
 
AM/  PM 
 
 
 
 
Day 20 
 
 
AM/  PM 
 
 
 
 
Day 21 
 
 
AM/  PM 
 
 
 
 

 
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Version Date: 11/30/2021 
 
Cycle #: _____    Start Date: |__/__|__/__|__/__|       End Date: |__/__|__/__|__/__|              Dose Level:            mg/m2 
WEEK 4 
Comments 
(Describe any missed or extra doses, vomiting and/or bothersome effects.) 
Day 22 
 
Day 23 
 
Day 24 
 
Day 25 
 
Day 26 
 
Day 27 
 
Day 28 
 
If this form will be used as a source document, the site personnel who administered the study drug must sign and date 
this form below: 
 
Signature: ________________________________________          Date: __________________________ 
 
     (site personnel who administered the study drug) 
 

 
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APPENDIX IV: PALBOCICLIB DOSING NOMOGRAM 
Drug doses should be adjusted based on the BSA calculated from height and weight measured within 7 
days prior to the beginning of each cycle.  
 
Palbociclib Dose Assignment: 75 mg/m2/dose PO once daily (max dose 125 mg) 
 
BSA (m2) 
Palbociclib 
dose (mg/dose) 
Dose Reduction for 
Toxicity (mg/dose) 
0.87-1.16 
75 
Off Protocol Therapy 
1.17-1.5 
100 
75 
≥ 1.51 
125 
100 
 
 

  
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Cycle 1  
APPENDIX V: APEC1621I THERAPY DELIVERY MAP 
Therapy Delivery Map – Cycle 1 
This Therapy Delivery Map (TDM) relates to Cycle 1. Each cycle lasts 28 days.  
____________________________ 
Patient COG ID number 
_______________________ 
Accession number 
Criteria to start each cycle are listed in Section 5.2. Extensive treatment details are in Section 5.1. 
 
 
DRUG 
ROUTE DOSAGE 
DAYS IMPORTANT NOTES 
Palbociclib 
 
Do not use 
commercial 
supply. 
PO 
Dose Level : 75 mg/m2(max 
dose 125 mg) 
 
Refer to the dosing 
nomogram. 
1-21 
Drug doses should be adjusted based on the BSA 
calculated from height and weight measured within 7 
days prior to the beginning of each cycle and according 
to the dosing nomogram in Appendix IV. Palbociclib 
will be given by mouth once daily with food on Days 1-
21, then rest for 7 days. Take at approximately the same 
time each day. 
 
If vomiting occurs after taking the dose, the dose should 
NOT be repeated and the next dose should be 
administered at the regularly scheduled time. 
 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
Palbociclib 
_________ mg 
Studies 
 
 
 
Enter calculated dose above as per 
dosing nomogram and actual dose 
administered below 
 
 
 
1 
_________ mg 
  
 
 
2 
_________ mg 
 
 
 
3 
_________ mg 
 
 
 
4 
_________ mg 
c 
 
 
5 
_________ mg 
 
 
 
6 
_________ mg 
 
 
 
7 
_________ mg 
  
 
 
8 
_________ mg 
a, c, d, e, m 
 
 
9 
_________ mg 
 
 
 
10 
_________ mg 
 
 
 
11 
_________ mg 
 
 
 
12 
_________ mg 
c 
 
 
13 
_________ mg 
 
 
 
14 
_________ mg 
 
 
 
15 
_________ mg 
a, c, d, e, m 
 
 
16 
_________ mg 
 
 
 
17 
_________ mg 
 
 
 
18 
_________ mg 
c 
 
 
19 
_________ mg 
 
 
 
20 
_________ mg 
 
 
 
21 
_________ mg 
 
 
 
22 
Study Drug not Administered on Days 22-
28 
a, c, d, e, m 
 
 
23 
Study Drug not Administered on Days 22-
28 
 
 
 
24 
Study Drug not Administered on Days 22-
28 
 

  
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Cycle 1  
 
 
25 
Study Drug not Administered on Days 22-
28 
c 
 
 
26 
Study Drug not Administered on Days 22-
28 
 
 
 
27 
Study Drug not Administered on Days 22-
28 
 
 
 
28/1 
Study Drug not Administered on Days 22-
28 
a, b, d, e, f , g  
 
See Section 6.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care 
Guidelines. 
 
 
Required Observations in Cycle 1  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below. For information related to prestudy observations, please refer to section 8.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                                            
      
 
 
 
 
 
a. 
History/Physical Exam (including VS) 
b. Ht/Wt/BSA 
c. 
CBC/differential/platelets- If patients have Grade 4 neutropenia then CBCs should be 
checked at least every other day until recovery to Grade 3 or until meeting the criteria 
for dose limiting toxicity.  If patients develop Grade 3 or greater thrombocytopenia 
then CBCs should be checked every 3 to 4 days until recovery per section 6.1. 
d. Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, bilirubin 
f. 
Albumin 
g. Patient Diary- (see Appendix III) should be reviewed after completion of each 
treatment cycle and uploaded into RAVE. The patient diary should be collected and 
reviewed weekly. 

  
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Cycle 1  
 
This listing only includes evaluations necessary to answer the primary and secondary aims. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
Treatment Details: Cycle 1 
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are 
met (whichever occurs later).  
 

  
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Subsequent Cycles 
All Subsequent Cycles
 
Therapy Delivery Map – All Subsequent Cycles 
This Therapy Delivery Map (TDM) relates to all subsequent cycles. Each cycle lasts 28 
days. Treatment may continue in the absence of disease progression or unacceptable 
toxicity. Use a copy of this page once for each cycle (please note cycle number below).  
____________________________ 
Patient COG ID number 
_______________________ 
Accession number 
 
Criteria to start each cycle are listed in Section 5.2. Extensive treatment details are in Section 5.1. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS IMPORTANT NOTES 
Palbociclib 
 
Do not use 
commercial 
supply.  
PO 
Dose Level : 75 mg/m2(max 
dose 125 mg) 
 
Refer to the dosing 
nomogram. 
1-21 
Drug doses should be adjusted based on the BSA 
calculated from height and weight measured 
within 7 days prior to the beginning of each cycle 
and according to the dosing nomogram in 
Appendix IV. Palbociclib will be given by mouth 
once daily with food on Days 1-21, then rest for 7 
days. Take at approximately the same time each 
day. 
 
 
If vomiting occurs after taking the dose, the dose 
should NOT be repeated and the next dose should 
be administered at the regularly scheduled time. 
 
Enter Cycle #: _____  
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
Palbociclib 
________ mg 
Studies 
 
 
 
Enter calculated dose above as per dosing 
nomogram and actual dose administered 
below 
 
 
 
1 
_________ mg 
a,b,d,e,f,i 
 
 
2 
_________ mg 
 
 
 
3 
_________ mg 
 
 
 
4 
_________ mg 
 
 
 
5 
_________ mg 
 
 
 
6 
_________ mg 
 
 
 
7 
_________ mg 
 
 
 
8 
_________ mg 
c 
 
 
9 
_________ mg 
 
 
 
10 
_________ mg 
 
 
 
11 
_________ mg 
 
 
 
12 
_________ mg 
 
 
 
13 
_________ mg 
 
 
 
14 
_________ mg 
 
 
 
15 
_________ mg 
c 
 
 
16 
_________ mg 
 
 
 
17 
_________ mg 
 
 
 
18 
_________ mg 
 
 
 
19 
_________ mg 
 
 
 
20 
_________ mg 
 
 
 
21 
_________ mg 
 
 
 
22 
Study Drug not Administered on Days 
22-28 
c 
 
 
23 
Study Drug not Administered on Days 
22-28 
 

  
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Subsequent Cycles 
 
 
24 
Study Drug not Administered on Days 
22-28 
 
 
 
25 
Study Drug not Administered on Days 
22-28 
 
 
 
26 
Study Drug not Administered on Days 
22-28 
 
 
 
27 
Study Drug not Administered on Days 
22-28 
 
 
 
28/1 
Study Drug not Administered on Days 
22-28 
a,b,d,e,f, g*, h*,i, j*  
See Section 6.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines 
* Please refer to section 8.1 for the specific timing of these observations 
 
Required Observations in All Subsequent Cycles 
 
a. 
History/Physical Exam (including VS) 
b. Ht/Wt/BSA 
c. 
CBC/differential/platelets- If patients have Grade 4 neutropenia then CBCs should be 
checked at least every other day until recovery to Grade 3 or until meeting the criteria 
for dose limiting toxicity. If patients develop Grade 3 or greater thrombocytopenia 
then CBCs should be checked every 3 to 4 days until recovery per section 6.1. 
d. Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, bilirubin 
f. 
Albumin 
g. Tumor Disease Evaluation – Every other cycle x 3 then q 3 cycles. Tumor Disease 
Evaluation should be obtained on the next consecutive cycle after initial 
documentation of either a PR or CR.  Subsequent scans may restart 2 cycles after the 
confirmatory scan. If the institutional investigator determines that the patient has 
progressed based on clinical or laboratory evidence, he/she may opt not to confirm 
this finding radiographically. Refer to Section 8.1 for more detailed information.  
h. Bone Marrow Aspirate and/or biopsy- Only required in patients suspected of having 
bone marrow metastasis on the basis of history, symptoms, laboratory evaluation or 
other clinical data. Should only be performed on patients with known bone marrow 
involvement at baseline. Refer to section 8.1 for more detailed information. 
i. 
Patient Diary- (see Appendix III) should be reviewed after completion of each 
treatment cycle and uploaded into RAVE. The patient diary should be collected and 
reviewed weekly.  
j. 
Circulating Tumor DNA (ctDNA-optional)- With consent, two samples will be 
collected on this protocol (Cycle 5 Day 1; and for patients receiving ≥ 5 cycles,  at 
progression or end of protocol therapy) see Section 8.3 for details of the ctDNA 
studies. 
 
 
 
 
 
 
 
 
 
 
 

  
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Subsequent Cycles 
 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE. 
 
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
Treatment Details: Subsequent Cycles 
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are 
met (whichever occurs later).  

  
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APPENDIX VI CORRELATIVE STUDIES 
 
 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total 
Cycle 5 
Day 1 
Circulating 
tumor DNA 
analysis 
(optional) 
8.3 
• 
For patients ≥ 10 kg collect 20 
mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg 
collect 10 mL (one tube)  
• 
For patients < 5 kg research 
samples will not be collected  
 
10 -20 
mL 
Streck Cell-Free DNA BCT 
tubes 
Total Blood Volume in 
Cycle 5 Day 1 
 
10-20 
mL 
 
 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total  ‘Time of 
progression’ or ‘End 
of protocol therapy’ 
Circulating 
tumor DNA 
analysis 
(optional) 
8.3 
• 
For patients ≥ 10 kg collect 20 
mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg 
collect 10 mL (one tube)  
• 
For patients < 5 kg research 
samples will not be collected  
 
10-20 mL 
Streck Cell-Free 
DNA BCT tubes 
Total Blood Volume in 
‘Time of progression or 
End of protocol therapy’ 
 
10-20 mL 
 
 
 
 
 
 

  
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APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621I EXPANSION COHORTS 
Target tumor types considered for biomarker-positive expansion cohorts in the event of agent activity 
in a specific tumor type. 
 
 
 
 
 
Tumor type 
1. Ependymoma 
2. Ewing Sarcoma/Peripheral PNET 
3. Hepatoblastoma 
4. Glioma, high grade 
5. Glioma, low grade 
6. Langerhans Cell Histiocytosis 
7. Malignant Germ Cell Tumor 
8. Medulloblastoma  
9. Neuroblastoma 
10. Non-Hodgkin Lymphoma 
11. Non-RMS Soft Tissue Sarcoma 
12. Osteosarcoma 
13. Rhabdoid Malignancy 
14. Rhabdomyosarcoma 
15. Wilms Tumor 
16. Other Histology (based on COG/NCI-CTEP approval) 

  
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APPENDIX VIII: EXAMPLES OF ACTIONABLE MUTATIONS OF INTEREST FOR APEC1621I 
 
 
INCLUSION 
VARIANTS 
  
CNV 
  
  
Gene Name 
Variant Type 
LOE 
CDK4 
Amplification 
2 
CDK6 
Amplification 
2 
CCND1 
Amplification 
2 
CCND2 
Amplification 
2 
CCND3 
Amplification 
2 
One of the above amplifications AND 
IHC 
RESULTS 
GENE: 
STATUS: 
RB 
POSITIVE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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APPENDIX IX APEC1621I YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621I 
(for children from 7 through 12 years of age) 
 
We want to tell you all about this study. You and your family can decide if you want to be in it. 
Ask questions if you don’t understand. 
 
1. What is the name of the study? A study of Molecular Analysis for Therapy Choice (MATCH) 
in children with a cancer that has come back after treatment or is difficult to treat 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is 
being done at other hospitals. 
 
3. What is the study about? We are asking you to take part in a research study because other 
treatments did not get rid of the cancer. A research study is when doctors work together to try out 
new ways to help people who are sick. In this study, we are trying to learn more about how to 
treat the kind of cancer you have.  
 
4. What will happen to me in the study? Children who are part of this study have been “matched” to 
a medicine. We think that this medicine will help you and other kids that have the same kind of 
cancer as you have. If you decide to be treated with this medicine, you will have some tests and 
check-ups done more often than if you weren’t part of this study. We will follow your health after 
you finish the study treatment. 
 
Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is for your cancer to 
stop growing, or even shrink, but we don’t know for sure if there is any benefit of being part of this 
study. 
 
Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that you may have more problems, or side 
effects, from a medicine used in this study. There may be risks that we don’t know about yet. 
 
5. Do I have to be in the study? You and your family can choose to be part of this study or not. You 
and your family can also decide to stop being in this study at any time once you start. There may 
be other treatments for your illness that your doctor can tell you about. If you have any questions 
or don’t like what is happening, please tell your parent, the doctor or nurse. 
 
6. We are asking your permission to collect additional tumor tissue. We want to see if there are 
ways to tell how the cancer will respond to treatment. These samples would be taken on tumor 
samples that we already have, so there would be no extra procedures. This would not change what 
medicines we would use to treat your tumor and would not provide any “benefits” to you. We 
hope that it might help us learn how to better treat other children’s cancers in the future. You do 
not have to participate if you do not want to. 
 
 

  
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INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621I 
(for teens from 13 through 17 years of age) 
A study of Molecular Analysis for Therapy Choice (MATCH) in children 
with a cancer that has come back after treatment or is difficult to treat 
 
1. What is the name of the study? A study of Molecular Analysis for Therapy Choice (MATCH) in 
children with a cancer that has come back after treatment or is difficult to treat  
 
2.   Who is in charge of the study? The study is being done by Children’s Oncology Group and is being 
done at other hospitals. 
 
3. What is the study about? We are asking you to take part in a research study because other treatments 
did not get rid of the cancer. A research study is when doctors work together to try out new ways to 
help people who are sick. In this study, we are trying to learn more about how to treat the kind of cancer 
that you have.  
 
4.  What will happen to me on the study? Your tumor has a mutation that matches palbociclib, and so you 
have been assigned to palbociclib. The doctors want to see if palbociclib will make children with your 
type of cancer get better. We don’t know if palbociclib will work well to get rid of your cancer. That is 
why we are doing the study. 
 
Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that palbociclib may cause 
your cancer to stop growing or to shrink for a period of time but we don’t know for sure if there is any 
benefit of being part of this study. 
 
Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The primary risk to you from this study is that you may have side effects, from 
palbociclib. Your doctor will talk to you about the risks we know about from palbociclib. There may 
be other risks from palbociclib that we don’t know about yet. 
 
5.  Will I be paid to be in this study? You will not be paid for being in this study.  
 
6. Do I have to be in the study? You and your family can choose to be part of this study or not. You and 
your family can also decide to stop being in this study at any time once you start. There may be other 
treatments for your illness that your doctor can tell you about. If you have any questions or don’t like 
what is happening, please tell your parent, the doctor or nurse. 
 
7.   We are asking your permission to collect additional tumor tissue. We want to see if there are ways to 
tell how the cancer will respond to treatment. These samples would be taken on tumor samples that we 
already have, so there would be no extra procedures. This would not change what medicines we would 
use to treat your tumor and would not provide any “benefits” to you. We hope that it might help us 
learn how to better treat other children’s cancers in the future. You do not have to participate if you do 
not want to. 
 
 
 
 
 
 
 

  
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APPENDIX X CTEP AND CTSU REGISTRATION PROCEDURES 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program 
(CTEP) Identity and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam. In 
addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator 
(NPIVR), or Associate Plus (AP) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the  Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs 
must list all clinical practice sites and Institutional Review Boards (IRBs) covering their practice 
sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
 

  
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In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must be rostered 
at the enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at https://ctep.cancer.gov/
investigatorResources/default.htm. For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov. 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents is 
restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Protocol Organization (PO) 
on the protocol. One way to search for a protocol is listed below.  
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select COG, and 
protocol number (*insert study number*). 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.) 
 
Protocol-Specific Requirements For Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Checking Your Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website.  

  
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• 
Click on Regulatory  at the top of the screen; 
• 
Click on Site Registration; and  
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
Data Submission / Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and 
role assignments.  
 
Requirements to access Rave via iMedidata: 
• A valid CTEP-IAM account; and  
• Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration 
type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password and click 
on the accept link in the upper right-corner of the iMedidata page. Site staff will not be able to 
access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be accessed 
by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning is required 
and has not yet been taken, the link to the eLearning will appear under the study name in iMedidata 
instead of the Rave EDC link; once the successful completion of the eLearning has been recorded, 
access to the study in Rave will be granted, and a Rave EDC link will display under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to 

  
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activate their account. Account activation instructions are located on the CTSU website in the Data 
Management section under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are available 
to access details and reports of unanswered queries, delinquent forms, and timeliness 
reports. Review the DQP modules on a regular basis to manage specified queries and 
delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization for delinquent form details and reports to be available on the 
DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.   
 
 
 
 
 
 
 
 
 
 
 

  
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APPENDIX XI PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drug, Palbociclib.  This clinical trial is sponsored by the National Cancer Institute.  This form is addressed 
to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
Palbociclib interacts with certain specific enzyme(s) in your liver. The enzyme in question is [CYP3A, and 
Palbociclib is broken down by this enzyme and may be affected by other drugs that inhibit or induce this 
enzyme. 
   
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Palbociclib may interact with other drugs, which can cause side effects. For this reason, it is very important 
to tell your study doctors of any medicines you are taking before you enroll onto this clinical trial.  It is also 
very important to tell your doctors if you stop taking any regular medicines, or if you start taking a new 
medicine while you take part in this study.  When you talk about your current medications with your doctors, 
include medicine you buy without a prescription (over-the-counter remedy), or any herbal supplements 
such as St. John’s Wort.  It is helpful to bring your medication bottles or an updated medication list with 
you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
 
Palbociclib must be used very carefully with other medicines that use certain liver enzymes.  Before you 
enroll onto the clinical trial, your study doctor will work with your regular health care providers to review 
any medicines and herbal supplements that are considered “strong inducers or inhibitors of CYP3A.” 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
• 
Avoid use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, and voriconazole). Avoid grapefruit or grapefruit juice during 
palbociclib treatment. Avoid use of strong CYP3A inducers (e.g., phenytoin, rifampin, 
carbamazepine, enzalutamide, and St John's Wort). 
 
• Your regular health care provider should check a frequently updated medical reference or call your 
study doctor before prescribing any new medicine or discontinuing any medicine.  Your study 
doctor’s name is  _____________________________________ and he or she can be contacted at 
             _____________________________________. 
 
 

  
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STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
palbociclib.  This clinical trial is sponsored by the NCI.  Palbociclib  
may interact with drugs that are processed by your liver or use certain 
transport proteins in your body.  Because of this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
➢ No grapefruit juice, Seville oranges, or grapefruit can be consumed 
while on palbociclib. 
 
 
 
 
Palbociclib interacts with specific liver enzymes called CYP3A and 
must be used very carefully with other medicines that interact with 
these enzymes.  
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong 
inducers or inhibitors of CYP3A.”  
➢ The use of proton pump inhibitors (PPIs) must be avoided if 
possible while taking palbociclib. Your study doctor will review any 
medicines you are taking. 
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently updated medical reference for 
a list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

  
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APPENDIX XII TOXICITY-SPECIFIC GRADING  
 
Bilirubin 
 
Grade 1: 
≤ 1.5 X ULN 
Grade 2: 
> 1.5 X ULN - 3X ULN 
Grade 3: 
> 3 X ULN -10X ULN 
Grade 4: 
> 10 X ULN 
 
ALT: For the purpose of this study, the ULN for SGPT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
≤ 135 U/L 
Grade 2: 
136 U/L - 225 U/L 
Grade 3: 
226 U/L - 900 U/L 
Grade 4: 
> 900 U/L 
 
AST: For the purpose of this study, the ULN for SGOT is 50 U/L regardless of baseline. 
 
Grade 1: 
≤ 150 U/L 
Grade 2: 
151 U/L -250 U/L 
Grade 3: 
251 U/L -1000 U/L 
Grade 4: 
> 1000 U/L 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 X ULN - 5X ULN 
Grade 3: 
> 5 X ULN -20X ULN 
Grade 4: 
> 20 X ULN