Clinical trial NCT01553149
Conditions: Neurofibromatosis Type 1 Recurrent Childhood Pilocytic Astrocytoma Recurrent Childhood Visual Pathway Glioma
Sponsor: National Cancer Institute (NCI)
Start date: 2012-07-05; Completion date: 2023-12-31
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well low-dose lenalidomide works compared with high-dose lenalidomide in treating younger patients with juvenile pilocytic astrocytomas or optic nerve pathway gliomas that have come back (recurrent), have not responded to treatment (refractory), or are growing, spreading, or getting worse (progressive). Lenalidomide is classified as an immunomodulatory drug as it boosts the immune system. It has other potential anti-tumor effects, for example, it may stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether low-dose lenalidomide is more or less effective than high-dose lenalidomide in treating patients with juvenile pilocytic astrocytomas or optic nerve pathway gliomas.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the objective response rate in children with recurrent, refractory, or progressive juvenile pilocytic astrocytomas and optic pathway gliomas who are treated with Regimen A low-dose (20 mg/m\^2/dose) or Regimen B high-dose (115 mg/m\^2/dose) lenalidomide.

SECONDARY OBJECTIVES:

I. To estimate the event-free survival (EFS) (based on standard two-dimensional tumor measurements, determined by each institution) of children with recurrent, refractory, or progressive juvenile pilocytic astrocytomas and optic pathway gliomas who are treated with lenalidomide.

II. To compare response categories and EFS across the 3 magnetic resonance (MR) sequences (T2-weighted, fluid attenuated inversion recovery \[FLAIR\], T1-weighted post-contrast).

III. To correlate steady-state pharmacokinetics of lenalidomide (1 sample obtained between days 5-21) with objective response and EFS.

IV. To evaluate toxicities of long-term lenalidomide use.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (Regimen A): Patients receive low-dose lenalidomide orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.

ARM II (Regimen B): Patients receive high-dose lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up annually for approximately 3 years.

Arms: arm 1: Patients receive low-dose lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive high-dose lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Lenalidomide intervention 2: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol documents:
Prot_SAP_001.pdf: 
  
 
 
 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, M.S. 
crabtreed@email.chop.edu 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
June 1, 2018 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
 
 
Dear Ms. Kruhm, 
 
The Study Committee for ACNS1022, A Phase II Randomized Trial of 
Lenalidomide (NSC # 703813, IND #) in Pediatric Patients with Recurrent, 
Refractory or Progressive Juvenile Pilocytic Astrocytomas and Optic Pathway 
Gliomas, has provided Amendment #6 for CTEP review. 
 
The submission of this amendment is in response to an RRA from Dr. Howard 
Streicher (streicherh@ctep.nci.nih.gov). Revisions to the protocol are detailed in 
the summary of changes below. 
 
The ACNS1022 Study Committee looks forward to approval of this amendment. 
Please contact me with any questions or concerns. 
 
Sincerely, 
 
Nina Butingan, MBS, Protocol Coordinator (for) 
Katherine Warren, MD, ACNS1022 Study Chair 
Peter Adamson, MD, Children’s Oncology Group Chair 
 
 
 
 
 
 
 
 
 
 


  
 
ii 
 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
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 
Page(s) 
Change 
1. 
General 
 
The amendment number has been updated. 
2. 
General 
 
The version date has been updated. 
3. 
General 
 
The Study Chair’s phone number has been updated. 
4. 
Table of 
Contents 
2-4 
The Table of Contents has been updated. 
5. 
6.1 
30-37 
The drug monograph for lenalidomide has been updated. 
6. 
11.0 
51-55 
Changes have been made to the section based on CTCAE version 
5.0. 
 
 
 


 
 
 
 
ACNS1022 
 
1 
 
 
Activated: 
March 19, 2012 
Version Date: 
6/1/2018 
Closed: 
January 18, 2017 
Amendment #: 
6 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
ACNS1022 
 
A Phase II Randomized Trial of Lenalidomide (NSC # 703813, IND #) in Pediatric Patients 
with Recurrent, Refractory or Progressive Juvenile Pilocytic Astrocytomas and Optic 
Pathway Gliomas 
 
NCI Supplied Agent: Lenalidomide (IND# , NSC# 703813) 
 
A Groupwide Phase II Study  
 
 
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 
 
Katherine Warren, MD 
National Cancer Institute  
Pediatric Oncology Branch 
10 Center Drive, Bldg 10 CRC, Room 1-5750 
Bethesda, MD 20892-1102 
Phone: 
(240) 760-6202 
Fax: 
(301) 480-2308 
E-mail: 
warrenk@mail.nih.gov 
 
 
 


 
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Page 2 
 
 
TABLE OF CONTENTS 
SECTION 
PAGE 
TABLE OF CONTENTS 
2 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Objective 
9 
1.2 
Secondary Objectives 
9 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Angiogenesis in Childhood CNS Tumors 
10 
2.3 
Thalidomide 
11 
2.4 
Lenalidomide (CC-5013) 
11 
2.5 
Rationale for Pharmacokinetic Studies 
14 
2.6 
Rationale for Imaging Studies 
14 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
14 
3.1 
Study Enrollment 
14 
3.2 
Patient Eligibility Criteria 
18 
4.0 
TREATMENT PROGRAM 
23 
4.1 
Overview of Treatment Plan 
23 
4.2 
Concomitant therapy restrictions 
24 
4.3 
Lenalidomide Administration 
25 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
29 
5.1 
Non-Hematologic Toxicities 
29 
5.2 
Hematologic Toxicities 
29 
6.0 
DRUG INFORMATION 
30 
6.1 
LENALIDOMIDE (RevlimidTM, CC-5013, CDC-501) NSC# 703813, IND # 
(05/15/18) 
30 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
40 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
40 
7.2 
Follow-up 
41 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
41 
8.1 
Criteria for Removal from Protocol Therapy 
41 
8.2 
Off Study Criteria 
41 
9.0 
STATISTICAL CONSIDERATIONS 
42 
9.1 
Sample Size and Study Duration 
42 
9.2 
Study Design 
42 
9.3 
Methods of Analysis 
42 
9.4 
Analysis of Efficacy 
43 
9.5 
Monitoring for Efficacy 
43 
9.6 
Monitoring for Toxicity 
44 


 
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9.7 
Interim Monitoring of Toxic Death 
44 
9.8 
Analysis of Toxicity 
45 
9.9 
Analysis of Lenalidomide Pharmacokinetic Parameters 
45 
9.10 
Analysis of Standard MR Sequences 
45 
9.11 
Effect of the Stratification on Response Rate 
45 
9.12 
Gender and Minority Accrual Estimates 
46 
10.0 
EVALUATION CRITERIA 
46 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
46 
10.2 
Methodology to Determine Tumor Measurement 
46 
10.3 
Selection of Target and Non-Target Lesions 
49 
10.4 
Response Criteria for Target Lesions 
49 
10.5 
Response Criteria for Non-target Lesions 
50 
10.6 
Retrospective Response Review 
50 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
50 
11.1 
Purpose 
50 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
50 
11.3 
Specific Examples for Expedited Reporting 
51 
11.3.5 Pregnancy, Pregnancy Loss, and Death Neonatal 
52 
11.4 
Reporting Requirements for Specialized AEs 
53 
11.5 
Exceptions to Expedited Reporting 
53 
11.6 
Reporting Requirements - Investigator Responsibility 
54 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
54 
11.8 
Reporting Table for Late Phase 2 and Phase 3 Studies 
55 
11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
56 
11.10 
Routine Reporting of Adverse Events 
57 
12.0 
STUDY REPORTING AND MONITORING 
58 
12.1 
CDUS 
58 
12.2 
Data and Safety Monitoring Committee 
58 
12.3 
CRADA/CTA 
58 
13.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
60 
13.1 
Steady State Pharmacokinetic Study 
60 
14.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
61 
14.1 
Timing of MRIs 
61 
14.2 
MRI Guidelines for Brain/Spine Tumors 
61 
14.3 
Tumor Response Assessment 
62 
14.4 
Retrospective Central Review 
62 
APPENDIX I:  SITE COUNSELOR IDENTIFICATION FORM 
63 
APPENDIX II: LENALIDOMIDE RISKS OF FETAL EXPOSURE, PREGNANCY  
TESTING GUIDELINES AND ACCEPTABLE BIRTH CONTROL METHODS 
65 
APPENDIX III A: LENALIDOMIDE EDUCATION AND COUNSELING GUIDANCE 
DOCUMENT FOR FEMALE SUBJECTS 
70 
APPENDIX III B: LENALIDOMIDE EDUCATION AND COUNSELING GUIDANCE 
DOCUMENT FOR MALE SUBJECTS 
74 
APPENDIX IV: LENALIDOMIDE PATIENT CARD FOR PEDIATRIC PATIENTS 
76 
APPENDIX V:   LENALIDOMIDE INFORMATION SHEET 
77 


 
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APPENDIX VI: PATIENT DIARY FOR LENALIDOMIDE CAPSULE  
ADMINISTRATION 
79 
APPENDIX VII: ACNS1022 PHARMACOKINETIC STUDY FORM: STEADY STATE 
SAMPLES 
80 
APPENDIX VIII:  YOUTH INFORMATION SHEETS 
81 
APPENDIX IX:  REGIMEN A LENALIDOMIDE DOSING TABLES 
83 
APPENDIX X:  CTEP AND CTSU REGISTRATION PROCEDURES 
84 
REFERENCES 
86 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Katherine E. Warren, MD 
Jason R. Fangusaro, MD 
Pediatric Hematology/Oncology 
Pediatric Hematology/Oncology 
National Cancer Institute 
Childrens Memorial Hospital 
Pediatric Oncology Branch 
2300 Children's Plaza 
Bldg 10 CRC, Room 1-5750 
Chicago IL 60614 
10 Center Drive 
Phone: (773) 880-3660 
Bethesda MD 20892-1102 
Fax: 
(773) 880-3223 
Phone: (240) 760-6202 
E-mail:  jfangusaro@childrensmemorial.org 
Fax: 
(301) 480-2308 
 
E-mail: warrenk@mail.nih.gov 
Karen M. Gauvain, MD 
 
Pediatrics Hematology/Oncology 
STUDY VICE CHAIR 
Cardinal Glennon Children's Medical Center 
Daniel Charles Bowers, MD 
1465 S. Grand Blvd 
Hematology/Oncology 
St. Louis MO 63104 
University of Texas Southwestern Medical Center 
Phone: (314) 577-5638 
5323 Harry Hines Boulevard MC 9063 
Fax: 
(314) 268-4081 
Dallas TX 75390-9063 
E-mail: kgauvain@slu.edu 
Phone: (214) 648-3896 
 
Fax: 
(214) 648-3122 
Soumen Khatua, MD FAAP 
E-mail:  daniel.bowers@utsouthwestern.edu 
Pediatrics Hematology/Oncology 
 
MD Anderson Cancer Center 
STUDY STATISTICIAN 
Children’s Cancer Hospital 
Mark Krailo, Ph.D. 
1515 Holcombe Blvd, Unit 87 
Statistics 
Houston, TX 77030 
Children's Oncology Group - Operations Center 
Phone: (713) 792-6620 x3280  
222 E. Huntington Drive, Suite 100 
Fax: 
(713) 792-0608 
Monrovia, CA 91016 
E-mail: skhatua@mdanderson.org      
Phone: (626) 241-1520 
 
Fax: 
(626) 445-4334 
AeRang Kim, MD 
E-mail: mkrailo@childrensoncologygroup.org 
Hematology/Oncology 
 
Children's National Medical Center 
STUDY COMMITTEE MEMBERS 
Center for Cancer and Blood Disorders 
Esther Adebayo-Olojo, PhD, RPh 
111  Michigan Avenue, N.W. 
Pharmacy 
Washington DC 20010 
New York University Langone Medical Center 
Phone: (202) 476-4744 
560 First Avenue, Rm HN300 
Fax: 
(202) 476-5685 
New York NY 10016 
E-mail:  aekim@cnmc.org 
Phone: (212) 263-6936 
 
Fax: 
(212) 263-8939 
Kelly Anne Laschinger, MSN 
E-mail:  adebae01@nyumc.org 
Nursing 
 
Rainbow Babies and Childrens Hospital 
Charles G. Eberhart, MD PhD 
Pediatric Oncology 
Pathology 
11100 Euclid Ave 
Johns Hopkins University 
RB&C 6054 
720 Rutland Ave - Ross 558 
Cleveland OH 44106 
Neuropathology 
Phone: (216) 844-3345 x43919 
Baltimore MD 21205 
Fax: 
(216) 844-5431 
Phone: (410) 502-5185 
E-mail:  Kelly.Laschinger@UHhospitals.org 
Fax: 
(410) 955-9777 
 
E-mail:  ceberha@jhmi.edu 
 
 
 
 
 


 
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STUDY COMMITTEE MEMBERS 
PROTOCOL COORDINATOR 
 
Gilbert Vezina, MD 
 
Chris Williams-Hughes 
Diagnostic Imaging 
Children's Oncology Group - Operations Center 
Children's National Medical Center 
222 E. Huntington Drive, Suite 100 
The George Washington University 
Monrovia, CA 91016 
School Medicine and Health Sciences 
Phone: (660) 553-5049 
111 Michigan Ave NW 
Fax: 
(626) 445-4334 
Washington, DC 20010-2970 
E-mail:  chrismwhughes@att.net 
Phone:  (202) 476-3651 
 
Fax:  
(202) 476-3644 
Stephanie Badour 
E-mail:  gvezina@cnmc.org 
Clinical Research Associate 
 
British Columbia children’s hospital 
RESEARCH COORDINATOR 
4480 Oak Street, Room B315 
Austin Hamm 
Vancouver, BC V6H 3V4 
Children's Oncology Group - Operations Center  
Canada 
222 Huntington Dr.,Suite 100 
Phone:   (604) 875-2345 x 5975 
Monrovia, CA  91016 
Fax:  
 (604) 875-2911 
Phone: (626) 241-1501 
E-mail:  sbadour@cw.bc.ca 
Fax: 
(626) 445-4334 
 
E-mail:  ahamm@childrensoncologygroup.org 
 
 
 
 
 
 
 
 
 
 
AGENT NSC# AND IND#’s 
 
Lenalidomide NSC#703813  IND# 
 
 
 
 
 
 
SEE SECTION 13 FOR SPECIMEN SHIPPING ADDRESSES 


 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about your 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 
 
Given the poor outcome of patients with recurrent or refractory gliomas and the limited activity of most 
cytotoxic agents, new agents with novel mechanisms of action are needed. Inhibition of angiogenesis offers 
a new approach based upon the dependence of tumor growth on angiogenesis. Lenalidomide is an oral agent 
with both antiangiogenic and immunomodulatory activity that is well-tolerated in adults and children, and 
appears to have some activity in childhood CNS tumors. 
 
This study is a randomized comparison of response rate among patients with recurrent, refractory or 
progressive juvenile pilocytic astrocytomas and optic pathway gliomas who are treated with lenalidomide. 
Lenalidomide will be given either as a low dose (20 mg/m2/dose) or high dose (115 mg/m2/dose) regimen 
PO for 21 days of each 28 day cycle. Treatment will continue for a maximum of 26 cycles in the absence 
of disease progression or unacceptable side effects. Response will be evaluated prior to every other cycle 
for the first 13 cycles and prior to every third cycle for cycles 14-26. Correlation of steady state 
pharmacokinetic levels with patient outcome will be performed.   
 
 
 
 


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EXPERIMENTAL DESIGN SCHEMA
Note: Each cycle is 28 days
PD = Progressive Disease
SD = Stable Disease
PR = Partial Response
CR = Complete Response
PD
PD
SD,PR,CR
Study Entry
and Randomization
Off Protocol 
Therapy
Cycles 14-26 of Lenalidomide
115 mg/m2/day PO on Days 1-21
Response Evaluation
prior to
Cycles 16, 19, 22, 25 
and after Cycle 26
Off Protocol 
Therapy
Regimen B
Cycles 1-13 of Lenalidomide
115 mg/m2/day PO on Days 1-21
Response Evaluation
prior to
Cycles 3, 5, 7, 9, 11 and 13
Response Evaluation
prior to
Cycles 16, 19, 22, 25 
and after Cycle 26
PD
PD
Regimen A
Cycles 1-13 of Lenalidomide
20 mg/m2/day PO on Days 1-21
Response Evaluation
prior to
Cycles 3, 5, 7, 9, 11 and 13
Cycles 14-26 of Lenalidomide
20 mg/m2/day PO on Days 1-21
SD,PR,CR


 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Objective 
To determine the objective response rate of children with recurrent, refractory or progressive 
juvenile pilocytic astrocytomas and optic pathway gliomas who are treated with Regimen A 
low-dose 
(20 mg/m2/dose)  or Regimen B high-dose (115 mg/m2/dose) lenalidomide. 
 
1.2 
Secondary Objectives 
 
1.2.1 
To estimate the event-free survival (EFS) (based on standard two-dimensional tumor 
measurements, determined by each institution) of children with recurrent, refractory or 
progressive juvenile pilocytic astrocytomas and optic pathway gliomas who are treated with 
lenalidomide. 
 
1.2.2 
To compare response categories and EFS across the 3 MR sequences (T2-weighted, 
FLAIR, T1-weighted post-contrast).  
 
1.2.3 
To correlate steady state pharmacokinetics of lenalidomide (1 sample obtained between 
Days 5-21) with objective response and EFS. 
 
1.2.4 
To evaluate toxicities of long term lenalidomide use. 
 
 
2.0 
BACKGROUND 
2.1 
Introduction/Rationale for Development 
Brain tumors are the most common solid tumors of childhood, with an annual incidence of 
33 per 1,000,000 children. Low-grade gliomas are the most common, representing 1/3 of 
all childhood primary CNS tumors. While treatment of these lesions is somewhat 
controversial, the general consensus is that these lesions are best treated with surgical 
resection if this can be performed without significant sequelae. Frequently, complete 
resection is not feasible without significant morbidity. Five- and ten-year progression-free 
survival rates for children with incomplete resections are 50% and 38%, respectively.1, 2  
Radiation therapy and chemotherapy are utilized in the setting of incomplete resection, but 
radiation may be associated with significant side effects. In addition, in a recent analysis, 
adults with low-grade gliomas who received postoperative radiation therapy had an 
improved 5 year progression-free survival (PFS), but overall survival (OS) was not 
significantly different.3 In pediatric patients, particularly those younger than 10 years and 
those with neurofibromatosis type I (NF1), chemotherapy is frequently utilized in an effort 
to postpone radiation therapy and its accompanying neurotoxic effects. 
 
Low-grade gliomas are a histologically heterogeneous group of tumors. Significant 
interobserver variability has been documented for pathologic diagnosis and grading.4,5 This 
is further complicated by the fact that some tumors are diagnosed by biopsy alone, which 
may not be representative of the entire tumor. The course of the disease in patients with 


 
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low-grade gliomas can be unpredictable. While some patients are symptomatic, some 
lesions, particularly those associated with NF1, represent incidental findings and the 
disease may be indolent.  
 
The major goals for treating unresectable lesions are therefore prevention of tumor 
progression and ablation of associated symptoms, while minimizing side effects of 
treatment. Radiation therapy has been shown to have efficacy, but is associated with 
cognitive deficits, cerebrovascular sequelae, endocrinologic dysfunction and second 
malignancies. Many low-grade gliomas are chemosensitive tumors and chemotherapeutic 
regimens have been used to delay or avoid radiation therapy. Chemotherapeutic regimens 
that have resulted in objective responses and increased PFS for patients with low-grade 
gliomas include vincristine and carboplatin, and the combination procarbazine, lomustine, 
vincristine dibromodulcitol and 6-thioguanine.6,7 In a study of children with newly 
diagnosed low-grade gliomas with evidence of progression, 56% had an objective response 
to vincristine/carboplatin and PFS was 68 ± 7% at 3 yrs.8 In children with recurrent low-
grade gliomas, 52 ± 10% of assessable patients had an objective response to this 
chemotherapy regimen.6 However, these chemotherapeutic regimens are associated with 
significant toxicities, including allergic reactions to carboplatin. 
  
Temozolomide and weekly vinblastine are alternative chemotherapeutic regimens. In the 
COG Phase II study of temozolomide given on a 5-day every 28 day schedule to children 
with recurrent CNS tumors (A09701), 1/21 patients with low-grade glioma had an 
objective response.9 Despite this low objective response rate, 41% of patients remained on 
study for 12 courses with no evidence of progression. In a second study of children with 
progressive or recurrent low-grade gliomas treated with temozolomide on a 5/28 day cycle, 
11% of patients with optic pathway/pilocytic astrocytomas had a partial response and 38% 
had stable disease.10 Although it appears to have modest activity, temozolomide is 
associated with hematologic toxicity and a potential risk of second malignancy. In A09701, 
25% of patients had Grade 3 or 4 thrombocytopenia and 19% had Grade 3 or 4 neutropenia 
during cycle 1. 
 
Weekly vinblastine has also been studied in the recurrent setting. In a Phase II study of 
weekly vinblastine in children with recurrent or refractory low-grade gliomas, 57% 
completed 52 weeks of chemotherapy.11 Objective responses occurred in 40% of patients. 
Patients in this study were eligible at the time of first recurrence, and disease progression 
was defined radiographically by either GLPHQVLRQDO 25% increase) or 3-dimensional 
 40% increase) criteria, confirmed at 8 weeks. More than 50% of these patients required 
a dose reduction for toxicity. It is important to note that these Phase II studies were 
performed in a heterogeneous group of patients with small numbers, different eligibility 
requirements and different definitions of progression. Toxicity was fairly significant. 
 
Juvenile pilocytic astrocytomas are the most common low-grade glioma in the pediatric 
age group12,28, but, historically, low-grade gliomas have been consolidated into one 
diagnostic category for the purposes of clinical trials.  Biological data on low-grade 
astroctytomas has recently emerged, challenging this concept.   
 
2.2 
Angiogenesis in Childhood CNS Tumors 
Angiogenesis plays a role in tumor growth, including tumors of the CNS. Brain tumors 
have demonstrated intense neovascularization and produce potent angiogenic 
mediators.13,14 Several types of childhood CNS tumors, including low-grade astrocytic, 


 
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high-grade astrocytic, and embryonal tumors exhibit significant angiogenic activity.15 Over 
the last decade, several of the mechanisms involved in tumor-induced angiogenesis have 
been elucidated. The most direct of these mechanisms is the secretion of cytokines with 
angiogenic properties by the tumor cells. Examples of such cytokines include acidic and 
basic fibroblastic growth factor (D,E-FGF), angiogenin, vascular endothelial growth factor 
(VEGF), and tumor necrosis factor alpha (TNF-D).16-17 Alternately, tumor cells can release 
angiogenic peptides through the production of proteases and the subsequent breakdown of 
the extracellular matrix where some cytokines are stored (i.e. EFGF). Angiogenesis can 
also be induced indirectly through the recruitment of inflammatory cells (particularly 
macrophages) and their subsequent release of angiogenic cytokines (i.e. TNF-D, EFGF).18 
 
2.3 
Thalidomide 
Thalidomide is a drug with a broad spectrum of activity, including anti-angiogenic 
properties. It inhibits growth factor-mediated neovascularization, is a known inhibitor of 
TNF-D, and has demonstrated inhibition of tumor growth in solid tumor models. 
Thalidomide costimulates T cells in vitro, inducing cytokine production (including IL-2 
and IFN-J) and cytotoxic responses.19 In clinical trials of this agent in adults with recurrent 
high-grade gliomas, some anti-tumor activity was observed (4/36 objective radiographic 
responses in one study, with 12/36 stable disease (SD) for minimum of 2 months), although 
the overall response rate was low.20,21 
 
2.4 
Lenalidomide (CC-5013) 
Lenalidomide is a potent analog of thalidomide and is classified as an immunomodulatory 
agent. Like thalidomide, it exerts a broad spectrum of pharmacologic and immunologic 
effects. Lenalidomide has been shown to be more potent than thalidomide in stimulating 
proliferation of T cells following primary induction by T-cell receptor (TCR) activation, 
and more potent than thalidomide in augmenting production of IL-2 and IFN-J following 
TCR activation of PBMC (IL-2) or T-cells (IFN-J). Lenalidomide also exhibits dose-
dependent inhibition of LPS-stimulated production of the pro-inflammatory cytokines 
TNF-D, IL-1E, and IL-6 by PBMC, and increased production of the anti-inflammatory 
cytokine IL-10 by LPS-stimulated PBMC. Lenalidomide up-regulates caspase 8 and down-
modulates leukocyte adhesion molecules. In contrast to thalidomide, lenalidomide 
stimulates activity of NK cells and induces G1 growth arrest of tumor cells. Lenalidomide 
exhibits significant antiangiogenic properties. It inhibits vascularization by inhibiting 
endothelial cell migration, rather than endothelial cell proliferation, and is an inhibitor of 
EFGF, VEGF, and TNF-D. (Investigator Brochure) 
  
Lenalidomide has been studied for use in patients with multiple myeloma, MDS, solid 
tumors and congestive heart failure. In Phase I clinical trials of lenalidomide in patients 
with multiple myeloma treated for 28 days at doses of 5 mg-50 mg per day, neutropenia 
and thrombocytopenia were the most common toxicities.22 Grade 4 neutropenia was 
observed in 1 patient at dose level 5 mg, 1 patient at dose level 25 mg; grade 3 neutropenia 
was observed in 2 patients at dose level 10 mg, 2 patients at dose level 25 mg and 4 patients 
at dose level 50 mg. Grade 3 thrombocytopenia was observed in 1 patient at each of the 
dose levels (5 mg, 10 mg, 25 mg, 50 mg). In an adult study of patients with solid tumors, 
16 patients with various solid tumors were enrolled at doses ranging from 5 mg/day –150 
mg/day for six weeks. 24,30 The majority of patients treated above 25 mg/day developed 
dose-limiting neutropenia or thrombocytopenia. Additional adverse events considered 
possibly, probably or definitely related to lenalidomide were mild to moderate in severity 


 
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and included rash, paresthesias, peripheral neuropathy, leg or hand cramps, taste 
disturbance, dry mouth, fever, nausea, vomiting, achiness, myalgias, generalized pains, 
bone pain, headache, itchy eye, constipation, bloating, cough, aphasia, tinnitus, 
pharyngitis, epistaxis, lightheadedness, shortness of breath, depression, night sweats, 
insomnia, dry skin, sinus congestion, urinary frequency, elevated SGOT, hyperuricemia, 
hyperglycemia, and elevated creatinine. 
  
In a Phase I study of lenalidomide administered daily to adults with refractory metastatic 
cancer (median age 66 yrs), an episode of thrombosis (dose-limiting) and Grade III 
hypotension was observed at a dose of 20 mg/day.23 Other toxicities (nausea, vomiting, 
diarrhea, rash, dizziness, peripheral neuropathy, fatigue, bone marrow suppression) were 
mild. In a second study of lenalidomide in adults with solid tumors (primarily melanoma 
and renal cell carcinoma), daily doses of 5-150 mg/day were well tolerated. Grade 4 
neutropenia was observed in 2 patients receiving > 50 mg/day.24 In a Phase I study in adults 
with recurrent high-grade gliomas, lenalidomide at doses of 40 mg/day x 21 days was well 
tolerated and no MTD was defined. This dose of 40 mg daily was predetermined to be the 
maximum dose to be tested in the adult glioma population based on some, but not all, prior 
3KDVH,DGXOWVWXGLHVZKLFKGHPRQVWUDWHGP\HORVXSSUHVVLRQDWGRVHV 50 mg/day. 
  
A Phase I study of lenalidomide was recently performed within the COG in pediatric 
patients with relapsed or refractory solid tumors or myelodysplastic syndrome. 
(ADVL0319) The primary objectives were to determine the maximum tolerated dose and 
recommended Phase II dose for children with refractory solid tumors and describe the 
toxicities in this population. Doses up to 70 mg/m2/day x 21 days followed by a 7-day rest 
were evaluated. Although 6 episodes of dose-limiting toxicity (DLT) were observed, they 
were sporadic and not clearly associated with dose. These DLTs included Grade 3 
hypercalcemia, Grade 3 hypophosphatemia, Grade 3 hypokalemia, Grade 4 neutropenia, 
Grade 3 somnolence, and Grade 3 urticaria and occurred at doses ranging from 15 mg/m2 
to 55 mg/m2. 29 No MTD was reached. The majority of patients on this study did not receive 
more than one course of therapy. 
  
A Phase I trial of lenalidomide in pediatric patients with recurrent, refractory or progressive 
CNS tumors performed within the Pediatric Brain Tumor Consortium (PBTC-018) has 
recently closed to accrual.25 Fifty-one patients were enrolled; 44 patients are evaluable for 
toxicity and response. Patients were treated at doses of 15-116 mg/m2/day for 21 days 
followed by a 7 day rest period (one course is 21 days of therapy + 7 day break). A 
maximum tolerated dose has not been reached. The agent has been well tolerated. Two 
DLTs were reported with an unclear association with lenalidomide. One patient treated at 
the 20 mg/m2/day dose level had cardiac dose limiting toxicity with a presumed myocardial 
infarct and elevated troponin. This patient had multiple risk factors for thromboembolism. 
One patient at dose level 68 mg/m2/day had dose-limiting fatigue but had concurrent 
disease progression. Twenty-three patients, representing all dose levels, received 6 or more 
courses of treatment and 9 patients have received 12 or more courses to date. 
 
On this study (PBTC-018), myelosuppression was the primary toxicity and occurred 
sporadically. No patient had Grade 4 myelosuppression during Course 1. 
0\HORVXSSUHVVLRQIRUSDWLHQWVWUHDWHGIRUF\FOHVZDVDOVRVSRUDGLFDQGQRWFOHDUO\
associated with dose, although data at the higher dose levels shows a possible trend toward 
moUHIUHTXHQWHSLVRGHVRI*UDGHVDQGP\HORVXSSUHVVLRQDWGRVHOHYHOVPJP2/day. 
Other common toxicities include fatigue (30%), gastrointestinal symptoms including 


 
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nausea (10%), emesis (4%), diarrhea (16%), and constipation (8%), as well as rash (14%) 
and muscle cramping (10%). It is also unclear if responses were dose-related. Objective 
responses (two partial responses, diagnoses JPA, OPG) were reported at doses of 
mg/m2/day. Of note, nine patients with recurrent, refractory or progressive optic pathway 
gliomas enrolled on study have received 8, 12+, 24, 24, 12, 13, 11 and 11+ cycles of therapy 
to date. Dose levels for these patients ranged from 15-116 mg/m2/day. Of 12 patients with 
-3$KDYHUHFHLYHG 6 courses to date at doses ranging from 68-116 mg/m2/day. Other 
patients with low-grade gliomas, including third ventricular astrocytomas (2 patients) and 
ganglioglioma (1 patient) have received 22, 24 and 12 courses, respectively. No patient 
with glioblastoma (n=4) received more than one course of therapy. Results from 
pharmacokinetic analysis show a linear relationship between lenalidomide dose and Cmax 
and AUC24 hrs.  
 
Early phase clinical trials of noncytotoxic (eg, antiangiogenic) agents in patients with brain 
tumors are complicated by several issues. Conventional endpoints in phase I trials are 
defined by predetermined toxicity criteria in order to define a maximum tolerated dose 
(MTD), or, more recently, by biologic endpoints in order to define a biologically effective 
dose. Standard phase I studies are designed to best identify acute, rather than long-term 
toxicities. Antiangiogenic agents frequently have little acute toxicity and may need to be 
administered chronically. They may be effective at doses well below the MTD and 
therefore dose escalations to the MTD may be unnecessary. However, defining a 
biologically effective dose is difficult as there is a lack of validated biological surrogate 
markers. Although objective responses were observed in the Pediatric Phase I trial at the 
higher dose levels and preliminary PK data suggests increasing exposure with increasing 
dose, it is unclear if response to this agent is dose related. We will therefore estimate 
activity in two cohorts, with patients receiving Regimen A low-dose (20 mg/m2/day) or 
Regimen B high-dose (115 mg/m2/day) lenalidomide. 
 
Efficacy of an agent in patients with brain tumors is historically defined in phase II trials 
by measuring response of the tumor based upon two-dimensional measurements using 
post-contrast MRI scans. These endpoints are neither ideal, nor applicable, when 
evaluating cytostatic agents, such as antiangiogenic agents, in patients with CNS tumors, 
especially with tumors such as low grade gliomas, that have variable and sometimes 
heterogeneous enhancing patterns and frequently contain cystic areas. Time-dependent 
endpoints, such as time to tumor progression, may be more appropriate for this group of 
agents in this patient population. However, this can be complicated by the erratic growth 
patterns of low-grade gliomas. The majority of clinical studies estimating activity report 
objective response rate as the primary objective. We will therefore evaluate both objective 
response rate and event-free survival in this study. 
 
In summary, lenalidomide is a well-tolerated, novel agent that appears to have some 
activity in childhood CNS tumors. Although it has immunomodulatory, anti-inflammatory 
and antiangiogenic activity, its exact antitumor mechanism is unclear. It is unclear if a 
dose-response relationship exists or if the primary toxicity (myelosuppression) is dose-
related. Long-term toxicities have not been fully evaluated. Given its apparent activity 
profile in children with low-grade gliomas enrolled on the pediatric Phase I study (PBTC-
018), we are proposing a Phase II trial of lenalidomide in a subset of this population. Initial 
dosing will be 20 mg/m2/day on Regimen A and 115 mg/m2/day on Regimen B, which is 
the maximum dose evaluated in the PBTC-018 Phase I study. Two dose reductions will be 
allowed as long as the patient is deriving clinical benefit. Response as defined in this trial 


 
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will include the objective response rate and long term stable disease; EFS will also be 
determined and compared to the objective response rate. It is expected that a number of 
these patients will remain on therapy for an extended period of time and therefore the long-
term hematologic tolerability of this agent will be evaluated. 
 
2.5 
Rationale for Pharmacokinetic Studies 
In order to obtain more information regarding a potential dose-response relationship and 
to further determine if myelosuppression is dose-related, pharmacokinetic studies will be 
performed in all patients in this study. Steady state PK levels of lenalidomide will be 
performed prior to administering the daily dose any day between Days 5-21 on Cycle 1 and 
again between Days 5-21 on any cycle following a dose reduction. Correlation of steady 
state levels and best response at the patient dose will be performed. A single blood sample 
(2 ml in a heparinized tube) will be collected at up to three time-points and pharmacokinetic 
analyses will be performed using HPLC.   
 
2.6 
Rationale for Imaging Studies 
To date, there are no reliable biologic surrogate markers established in humans for the 
effect of lenalidomide in children with CNS tumors. It is unclear if objective response in 
patients with low grade gliomas correlates with progression-free survival. In this study, 
standard COG MRI sequences, including T2-weighted, FLAIR, and T1-weighted post 
contrast, will be retrospectively reviewed to compare response categories with event-free 
survival.  
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
3.1 
Study Enrollment 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the eRDE system once authorization for the 
release of protected health information (PHI) has been obtained. The COG patient 
ID number is used to identify the patient in all future interactions with COG. If you 
have problems with the registration, please refer to the online help.   
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol.  
 
Please see Appendix X for detailed CTEP Registration Procedures for Investigators 
and Associates, and CTSU Registration Procedures including: how to download site 
registration documents; requirements for site registration, submission of regulatory 
documents and how to check your site’s registration status. 
 
3.1.2 
IRB Approval 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB 
approval and supporting documentation to the Cancer Trials Support Unit (CTSU) 
Regulatory Office before they can be approved to enroll patients. Allow 3 business 
days for processing. The submission must include a fax coversheet (or optional 


 
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CTSU IRB Transmittal Sheet) and the IRB approval document(s). The CTSU IRB 
Certification Form may be submitted in lieu of the signed IRB approval letter. All 
CTSU forms can be located on the CTSU web page (https://www.ctsu.org). Any 
other regulatory documents needed for access to the study enrollment screens will 
be listed for the study on the CTSU Member’s Website under the RSS Tab.  
 
IRB/REB approval documents may be faxed (1-215-569-0206), E-mailed 
(CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.  
 
When a site has a pending patient enrollment within the next 24 hours, this is 
considered a “Time of Need” registration. For Time of Need registrations, in 
addition to marking your submissions as ‘URGENT’ and faxing the regulatory 
documents, call the CTSU Regulatory Helpdesk at: 1-866-651-CTSU. For general 
(non-regulatory) questions call the CTSU General Helpdesk at: 1-888-823-5923.  
 
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
members’ web site by entering credentials at https://www.ctsu.org. For sites under 
the CIRB initiative, IRB data will automatically load to RSS. 
 
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. This information will be provided to the CTSU Regulatory 
Office from the CIRB at the time the site’s Signatory Institution accepts the CIRB 
approval. The Signatory site may be contacted by the CTSU Regulatory Office or 
asked to complete information verifying the participating institutions on the study. 
Other site registration requirements (i.e., laboratory certifications, protocol-
specific training certifications, or modality credentialing) must be submitted to the 
CTSU Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.3 
Reservation Requirements 
CRAs/Site Investigators should refer to the COG website to determine if the study 
is currently open for accrual. If the study is active, a reservation can be made 
by following the steps below: 
1) Log in to https://www.ctsu.org and enter your CTEP IAM user name and 
password to access the CTSU members area.  Then, click on the following 
link: https://www.ctsu.org/OPEN_SYSTEM/. 
2) Then, click on ‘Connect to OPEN’ link, and finally on ‘Create New 
Registration’ link. 
3) After entering your Institution CTEP ID and protocol number, click on the 
‘Slot Availability Information’ link to see how many reservations are 
available for that study. 
4) If one or more is available, select step 0 under registration step and 
complete the remaining questions to obtain a reservation. 
  
Prior to obtaining informed consent for the clinical trial and enrolling a patient, a 
reservation must be made following the steps above. Reservations may be obtained 
24 hours a day through the OPEN system.  
 


 
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3.1.4 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on 
either the lead protocol organization (LPO) or participating organization roster. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. 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.  
 
Prior to accessing OPEN, site staff and the results from the rapid central pathology 
screening review have confirmed the patient is eligible. 
x 
All eligibility criteria have been met within the protocol stated timeframes. 
x 
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. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.1.5 
Timing 
Female patients of childbearing potential must have negative serum or urine 
pregnancy test (sensitivity of at least 25 mIU/mL) results performed within 10-14 
days and again within 24 hours prior to the anticipated start of protocol therapy. 
(Refer to Appendix II for definition of female children of childbearing potential 
[FCCBP]) Also see Exclusion Criteria in Section 3.2.9.3 regarding the requirement 
for female patients of childbearing potential to commit to complete abstinence or 
to be on two forms of effective birth control prior to, during, and following 
protocol therapy.  
 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than five (5) calendar days after the date of study 
enrollment. Patients who are started on protocol therapy on this Phase II study 
prior to study enrollment will be considered ineligible.  
 
3.1.5.1 Required Counseling 
FDA requires that each clinical trials site have two counselors (Investigators are 
not eligible) trained by Celgene through the Celgene Pregnancy Prevention 
Counselor Program-Pediatric (CPPCP-PED). The CPPCP-PED is available on the 
internet for each person who has completed the site counselor identification form 
(Appendix I) and registered with Celgene prior to completing the CPPCP-PED. 
Each patient/guardian must be counseled prior to dispensing lenalidomide and 


 
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documentation is kept in the patient’s records. Both the training certificates and 
the completed Lenalidomide Education and Counseling Guidance Documents are 
auditable documents and must be produced upon request. Counselors who wish to 
counsel patients for different protocols at the same site or for the same protocol at 
different silts should indicate this on the site counselor form. Please not that 
counselor training for pediatric patients is separate from training for adult patients. 
Counselors who previously obtained CPPCP certificates must complete pediatric 
version. CPPCP-PED, in order to counsel patients in NCI-sponsored pediatric 
studies. 
 
Examples of healthcare professionals that may be trained counselors include 
nurses, pharmacists and physicians. Investigators may not serve as designated, 
trained counselors for the purpose of this study. Trained counselors must complete 
training using the online program provided free by Celgene. After the training is 
complete, the counselors must generate a training certificate and provide it to the 
CTSU for documentation. Sites may not order lenalidomide until documentation for 
two trained counselors is provided to the appropriate office as instructed in the email 
from Celgene. Because it may take up to 7 days for training, it is suggested that 
counselors be identified at the onset of the protocol and receive training as soon as 
possible after IRB protocol approval. 
 
Following completion of training, the designated counselors will be responsible for 
counseling subjects prior to any treatment or the dispensing of lenalidomide to ensure 
that the subject has complied with all requirements including use of birth control and 
pregnancy testing and that the subject understands the risks associated with 
lenalidomide.  Information pertinent to the risks of lenalidomide that should be used 
as part of training can be found in the document entitled “Lenalidomide Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods” 
(Appendix II).    All investigators should be familiar with this document and the risks 
associated with lenalidomide.  Counseling must be documented by the completion of 
a Lenalidomide Education and Counseling Guidance Document (Appendix III).  No 
drug will be dispensed until counseling and completion of this document occurs.  A 
copy of this document must be maintained in the patient’s medical record. Counseling 
includes verification with the patient that required pregnancy testing was performed 
and results were negative. Pregnancy test results should be documented on the 
Lenalidomide 
Patient 
Card 
for 
Pediatric 
Patients 
(Appendix 
IV).  
A Lenalidomide Information Sheet (Appendix V) will be supplied with each 
medication dispense. 
 
Please Note: The counseling requirements for investigational use of lenalidomide 
are separate from the RevAssist program requirements in the United States and the 
RevAidSM program in Canada.  Participation in these two programs is not required, 
nor sufficient for use of the investigational lenalidomide product. 
 
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. 
 
3.1.6 
Randomization 


 
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Randomization will take place at the time a patient is entered On Study via eRDE. 
Patients will be assigned to receive one of two lenalidomide doses with equal 
probability: 20 mg/m2/day (Regimen A – low dose) or 115 mg/m2/day (Regimen 
B – high dose).  Patients will be stratified according to the number of prior 
regimens (2 or less regimens versus greater than 2 regimens). 
 
3.2 
Patient Eligibility Criteria 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived (per COG policy posted 5/11/01). All clinical and laboratory data 
required for determining eligibility of a patient enrolled on this trial must be available 
in the patient's medical/research record which will serve as the source document for 
verification at the time of audit.  
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
 
INCLUSION CRITERIA 
3.2.1 
Age 
Patients must be less than 22 years of age at the time of enrollment.  
 
3.2.2 
Body Surface Area (BSA) 
3DWLHQWVPXVWKDYHD%6$P2 at the time of study enrollment. 
 
3.2.3 
Diagnosis  
Patients must have a pilocytic astrocytoma or optic pathway glioma that has 
relapsed, progressed or become refractory to conventional therapy. Patients with 
neurofibromatosis (NF-1) are eligible. 
 
3.2.3.1 
Patients must have histologic verification of malignancy. Histologic confirmation 
for patients with optic pathway gliomas will not be required.  
 
3.2.3.2 
Patients must have measurable residual disease, defined as tumor that is 
measurable in two perpendicular diameters on MRI.  For a lesion to be considered 
measurable, it must be at least twice the slice thickness on MRI (i.e visible on more 
than one slice). 
 
3.2.3.3 Brain and Spine MRI 
To document the degree of residual tumor, the following must be obtained (see 
Section 14.0 for complete details): 
 
3.2.3.3.1 
All patients must have a brain MRI with and without contrast (gadolinium) 
within 1 week prior to study enrollment. For patients on steroids, baseline 
MRI scans must be performed after at least 1 week at a stable or decreasing 
dose of steroids. 
 
3.2.3.3.2 


 
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All patients with a history of spinal or leptomeningeal disease, and those 
patients with symptoms suspicious of spinal disease, must have a spine 
MRI with and without contrast (gadolinium) performed within 2 weeks 
prior to study enrollment. 
 
3.2.4 
Performance Level  
Patients must have a /DQVN\RU.DUQRIVN\SHUIRUPDQFHVWDWXVVFRUHRI60%. Use 
Karnofsky for patients > 16 years of age and Lansky for patients d 16 years of age. 
See https://members.childrensoncologygroup.org/prot/reference_materials.asp under 
Standard Sections for Protocols. 
 
3.2.5 
Prior Therapy 
 
3.2.5.1 
Patients must have been treated with at least one prior treatment regimen that  
included carboplatin. Patients who have received prior radiation therapy for this 
tumor are eligible. 
 
3.2.5.2 
Patients must have recovered (to CTC v.4.0 Grade 1 unless indicated below) 
from the acute toxic effects of all prior chemotherapy, immunotherapy, or 
radiotherapy prior to entering this study, with the exception of alopecia, weight 
changes and Grade I or II lymphopenia. 
a. Myelosuppressive chemotherapy: Must not have received within 3 weeks 
of entry onto this study (6 weeks if prior nitrosourea or mitomycin-C). 
b. Biologic (anti-neoplastic agent): At least 7 days after the last dose of a 
biologic agent.  For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended beyond 
the time during which adverse events are known to occur.   
c. Immunotherapy: At least 42 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines. 
d. Monoclonal antibodies: At least 3 half-lives of the antibody after the last 
dose of a monoclonal antibody. (See table on DVL homepage listing 
monoclonal antibody half-lives.) 
e. Radiation therapy (RT): Patients must have had their last fraction of 
craniospinal 
RT 
6 months prior to study entry and their last fraction of focal RT ZHHNV
prior to study entry. If the lesion used for on-study criteria is in the 
radiation field, there must be evidence of tumor progression after radiation 
therapy was completed. 
f. 
Study specific limitations on prior therapy: 
1) Patients who have received thalidomide are eligible if all acute 
thalidomide-related toxicity has resolved. 
2) Patients must not have received lenalidomide previously. 
 


 
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3.2.6 
Concomitant Medications Restrictions 
(Please see Section 4.2 for the concomitant therapy restrictions for patients during 
treatment.) 
 
a. 
Growth factor(s): Must not have received within 2 weeks of entry 
onto this study. 
b. 
Steroids: Patients who are receiving corticosteroids must be on a 
stable or decreasing dose for at least 1 week prior to baseline MRI.  
 
3.2.7 
Organ Function Requirements 
 
3.2.7.1 Adequate Bone Marrow Function Defined As: 
- 
Peripheral absolute neutrophil count (ANC) t 1000/PL  
- 
Platelet count t 100,000/PL (transfusion independent) 
- 
Hemoglobin t 8.0 g/dL (may receive RBC transfusions) 
 
3.2.7.2 Adequate Renal Function Defined As: 
- 
Creatinine clearance or radioisotope GFR t 70 mL/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
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 
\HDUV 
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. 
 
3.2.7.3 Adequate Liver Function Defined As: 
- 
Total bilirubin d 1.5 x upper limit of normal (ULN) for age, and 
- 
 SGPT (ALT) d 110 U/L.  For the purpose of this study, the ULN 
for SGPT is 45 U/L. 
- 
Serum albumin JG/. 
 
3.2.7.4 Adequate Pulmonary Function Defined As: 
- 
No evidence of dyspnea at rest and a pulse oximetry > 94% if there 
is clinical indication for determination. 
 
3.2.8 
Patients must be able to swallow intact capsules. 
 
 


 
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Page 21 
 
 
EXCLUSION CRITERIA 
 
3.2.9 
Pregnancy and Breast Feeding 
 
3.2.9.1 
Female patients who are pregnant are not eligible due to risks of fetal and 
teratogenic adverse events as seen in animal studies of lenalidomide. Lenalidomide 
is structurally related to thalidomide, which is known to cause severe life-
threatening birth defects in humans. 
 
3.2.9.2 
Lactating females are not eligible unless they have agreed not to breastfeed their 
infants while receiving protocol therapy and for 28 days after the last dose of 
lenalidomide. 
 
3.2.9.3 
Female patients of childbearing potential are not eligible unless they commit to 
complete abstinence or have been on 2 methods of birth control, including 1 highly 
effective method and 1 additional method at the same time (unless committing to 
complete abstinence of heterosexual intercourse) at least 28 days (4 weeks) prior 
to study enrollment. Sexually active females must also agree to remain on 2 
methods of birth control, during treatment (including during dose interruptions), 
and continuing for at least 28 days after the completion of protocol therapy. 
Examples of methods of contraception are as follows: 
x 
Highly effective methods (must use at least 1): 
 
Intrauterine device (IUD) 
 
Hormonal (prescription birth control pills, injections, 
implants) 
 
Tubal ligation 
 
Partner’s vasectomy 
 
x 
Additional effective methods: 
 
Male condom 
 
Diaphragm 
 
Cervical cap 
 
The two methods of birth control requirement applies to all sexually active females 
unless they have undergone a hysterectomy or bilateral oophorectomy. 
 
3.2.9.4 
Female patients of childbearing potential (including those who commit to complete 
abstinence) are not eligible unless they agree to ongoing pregnancy testing (see 
Section 4.1 for details) and counseling every 28 days about pregnancy precautions 
and risks of fetal exposure. 
 
 


 
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Page 22 
 
 
3.2.9.5 
Male patients of child fathering potential are not eligible unless they have agreed 
to use latex condoms during intercourse with a woman of childbearing potential 
while receiving treatment and for 28 days thereafter. 
 
3.2.10 Pre-existing conditions 
 
3.2.10.1 
Patients with a history of thromboembolism unrelated to a central line, or patients 
with a known predisposition syndrome for thromboembolism are not eligible. 
 
3.2.10.2 
Patients who have an uncontrolled or untreated infection are not eligible. 
 
3.2.10.3 
Patients with known overt cardiac disease, including but not limited to a history of 
myocardial infarction, severe or unstable angina, clinically significant peripheral 
vascular disease, Grade 2 or greater heart failure, or serious and inadequately 
controlled cardiac arrhythmia are not eligible. 
 
3.2.10.4 
Patients with a significant systemic illness that is not well-controlled in the opinion 
of the treating physician are not eligible. 
 
REGULATORY 
 
3.2.11 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.12 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 


 
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4.0 
TREATMENT PROGRAM 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 (except where explicitly 
prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
Upon enrollment, patients will be randomized to receive one of two treatments with 
lenalidomide; Regimen A (low dose) versus Regimen B (high dose). Please note there is a 
requirement for contraception for female patients of childbearing potential, such that they 
must commit to complete abstinence or agree to use two forms of effective contraception 
beginning at least 28 days prior to the first dose of lenalidomide and continuing until 28 
days after the last dose of lenalidomide. (See Section 3.2.9.4 and Appendix II). The primary 
study endpoint is objective response. Therapy may continue for a maximum of 26 cycles, 
in the absence of disease progression (see Section 10.4 for definition) if off protocol criteria 
have not yet been satisfied (see Section 8.1). 
 
Each cycle of therapy will last 28 days. Lenalidomide will be administered daily for the 
first 21 days of each cycle followed by a 7 day rest period. The lenalidomide dose for 
Regimen A will be 20 mg/m2/day by mouth daily and the dose for Regimen B will be 115 
mg/m2/day by mouth daily. The dose will be rounded to within 10% of the prescribed dose 
for convenience of capsule size. The calculated dose should be rounded in a manner to 
minimize the daily number of capsules.   
 
Patients or their guardians will keep a diary to document the intake of each dose of 
lenalidomide and potential side effects (see Appendix VI). Please instruct patient/parents 
to record each dose on the diary immediately rather than waiting until a later time. Errors 
on the diary should be crossed out and initialed. The patient diary should be reviewed with 
the patient and family at the completion of each treatment cycle, and drug should be 
accounted for at this time.  
 
Brain MRI will be performed at baseline (within 1 week prior to VWXG\HQUROOPHQWDQG
week on a stable or decreasing dose of steroids for those patients receiving steroids) and 
prior to each odd-numbered cycle (ie, prior to cycles 3, 5, 7, 9, 11, and 13) for the first 13 
cycles.  During cycles 14-26, imaging will be performed prior to every third cycle (ie, prior 
to cycles 16, 19, 22, and 25), after cycle 26, and as clinically indicated. See Section 14.0 
for imaging requirements. Patients with spine disease will also have spine MRI performed 
at the same timepoints after enrollment, (ie, prior to cycles 3, 5, 7, 9, 11, and 13) for the 
first 13 cycles.  During cycles 14-26, imaging will be performed prior to every third cycle 
(ie, prior to cycles 16, 19, 22, and 25), after cycle 26, and as clinically indicated. 
 
 


 
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Pharmacokinetic Study 
For all patients, a blood sample must be obtained prior to the daily dose between Day 5-21 
of cycle 1 at the time of routine safety lab monitoring. In the event of a dose reduction, a 
blood sample must also be obtained between Day 5-21 of the first cycle following each 
dose reduction. Please see Section 13.1 for details on pharmacokinetic sample collection 
and shipping. 
 
Required Pregnancy Testing During Study Participation 
Pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for female 
patients of childbearing potential, including those who commit to complete abstinence. If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 
days and then every 14 days while on study, when the patient is taken off protocol therapy, 
and at Days 14 and 28 following the last dose of lenalidomide. All other female patients of 
childbearing potential must have pregnancy tests weekly for the first 28 days of study 
participation and then every 28 days while on study, at the time the patient is taken off 
protocol therapy, and at Day 28 following the last dose of lenalidomide. If pregnancy or a 
positive pregnancy test does occur during protocol therapy, lenalidomide must be 
immediately discontinued. Pregnancy testing and counseling must be performed if a patient 
misses her period, if her pregnancy test is positive, or if her menstrual bleeding is abnormal.  
Lenalidomide treatment must be discontinued during this evaluation.  
 
Pregnancies and suspected pregnancies (including in the partner of a male study patient 
during study participation) must be reported as an adverse event. See Section 11.0 for 
adverse event expedited reporting guidelines for pregnancies and suspected pregnancies. 
 
Required Patient Education and Counseling 
Counseling about pregnancy precautions and the potential risks of fetal exposure will be 
conducted every 28 days, on Day 1 of each cycle. See Section 3.1.5.1 for counselor training 
requirements. Counseling must be completed prior to each dispensing of lenalidomide, and 
the counseling of each subject must be documented using the Lenalidomide Education and 
Counseling Guidance Document (Appendix III).   
 
See Section 7.1 for required observations prior to starting protocol therapy. 
 
4.2 
Concomitant therapy restrictions 
 
4.2.1 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients while on this study. The use of 
alternative or complementary therapies is discouraged. 
 
4.2.2 
Radiotherapy is not permitted. 
 
4.2.3 
Filgrastim (G-CSF) may be used at the treating physician’s discretion in patients with 
severe neutropenia (i.e. ANC <500ȝ/) to enhance neutrophil recovery when clinically 
indicated (for culture proven bacteremia or invasive fungal infections). Prophylactic or 
routine use of filgrastim in clinically well patients awaiting count recovery is not 
recommended. 


 
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Page 25 
 
 
 
4.2.4 
Corticosteroid therapy is permissible only for the treatment of increased intracranial 
pressure or physiologic replacement. The lowest dose consistent with good medical 
management should be used. Corticosteroids should NOT be used as an antiemetic due to 
their effect on the blood brain barrier. Patients on steroids who require an increase in steroid 
dose for worsening neurologic symptoms should have an MRI performed within 72 hours 
to rule out tumor progression. 
 
 4.2.5 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. Antiemetics should not be given 
prophylactically for cycle 1.  
 
4.2.6 
Anticonvulsants may be administered as clinically indicated.  However, it is unclear what 
effect, if any, lenalidomide has on anticonvulsant pharmacokinetics.  It is strongly 
recommended that anticonvulsant levels be checked at least weekly during the first course 
of therapy. 
 
4.2.7 
Drugs known to be pro-thrombotic (i.e. erythropoietic stimulating agents) should be 
avoided. 
 
For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard 
Sections for Protocols. 
 
4.3 
Lenalidomide Administration 
The lenalidomide cycle will be repeated every 28 days. Each cycle will be comprised of 
lenalidomide orally once daily for 21 days followed by 7 days without lenalidomide. 
Lenalidomide should be taken at approximately the same time each day.  One cycle of 
lenalidomide is described below. Lenalinomide is distributed by the NCI DTCD. Do 
not use commercially available drug. 
 
Begin Cycle 1 on Day 1 if ANC ȝ/, SODWHOHWFRXQWȝ/WUDQVIXVLRQ
independent), and upon the following: 
x 
confirmation of negative serum or urine pregnancy test (sensitivity of at least 25 
mIU/mL) in female patients of childbearing potential, 
x 
confirmation of the use of 2 forms of effective birth control for female patients of 
childbearing potential OR confirmation of commitment to complete abstinence, 
and 
x 
completion and documentation of required lenalidomide education and counseling 
(all patients) 
 
Dose calculations should be based on actual BSA and adjusted as necessary prior to 
each cycle. There is no maximum dosing. 
 


 
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Page 26 
 
 
Lenalidomide: PO once daily 
Days: 1 through 21. 
Dose:  Regimen A (Low Dose):  20 mg/m2/dose (See Appendix X for Dosing Tables) 
Regimen B (High Dose): 115 mg/m2/dose 
 
Note: The calculated dose should be rounded to within 10% of the prescribed dose for 
convenience of capsule size. The calculated dose should be rounded in a manner to 
minimize the daily number of capsules.  The dose should be given without food when 
possible, although this is not mandatory. If a patient vomits a dose within 10 minutes of 
administration and the capsules are clearly visible, the dose may be repeated. The capsules 
should be swallowed whole and not opened or chewed.  
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery maps (TDMs) for this cycle are on the next two pages. See Section 4.3.1 
for the Regimen A (Low Dose: 20 mg/m2/dose) therapy delivery map and Section 4.3.2 for 
the Regimen B (High Dose: 115 mg/m2/dose) therapy delivery map.  
 
Following completion of the first cycle, the lenalidomide cycle is repeated for up to a total 
of 26 cycles, as tolerated and in the absence of disease progression (see Section 10.4 for 
Response Evaluation). If disease progression occurs, the patient will be taken off protocol 
therapy.  
 
Susbequent lenalidomide cycles should begin on Day 29 or when $1&ȝ/, platelet 
count  ȝ/ WUDQVIXVLRQ LQGHSHQGHQW whichever occurs later, AND once the 
following criteria have been met: 
x 
confirmation of negative serum or urine pregnancy test (sensitivity of at least 25 
mIU/mL), 
x 
confirmation of the use of 2 effective methods of  birth control for female patients 
of childbearing potential OR confirmation of commitment to complete abstinence, 
x 
completion and documentation of required lenalidomide education and counseling 
(all patients). 


 
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Page 27 
 
 
 
4.3.1 
Lenalidomide Cycle – Regimen A (Low Dose: 20 mg/m2) 
Four consecutive weeks (28 days) will constitute one cycle (Lenalidomide daily x 21 days 
followed by 7 day rest). This therapy delivery map relates to all cycles of  Regimen A. Use a copy 
of this page once for each cycle. (Please note cycle number below.) 
________________________ 
Patient name or initials 
____________________________ 
DOB 
Criteria to start this cycle$1&,ȝ/DQGSODWHOHWFRXQWȝ/ (transfusion independent), confirmation of negative pregnancy test and the 
use of 2 methods of effective birth control for female patients of childbearing potential or commitment to complete abstinence, completion and 
documentation of required counseling. Details are in Section 4.0 (Treatment Overview). The Therapy Delivery Map for this cycle is on 1 page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Lenalidomide 
NSC#703813 
PO 
20 
mg/m2/dose 
1-21 
See admin guidelines in 
Section 4.3. (See 
Appendix IX for Dosing 
Tables) 
a. History, PE (Ht, Wt, VS), Performance Status 
b. CBC (differential, platelets) 
c. Urinalysis 
d. Electrolytes (inc BUN, Calcium, PO4, Magnesium)  
e. Creatinine; Total protein; Albumin, ALT, AST, bilirubi 
f. Pregnancy test (female pts of childbearing potential only) 
g. Brain MRI with and without gadolinium 
h. Spine MRI with and without gadolinium 
i. Pharmacokinetic study (see Section 13.0) 
j. Required Education and Counseling; Confirmation of birth 
control/abstinence  
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
PATIENT CARE 
Please Enter Cycle #: _____ Ht _________cm  
Wt _________kg  
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Lenalidomide 
____mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
____mg 
a, b@, c, d, e, f*, g#, h^, j 
 
 
 
2 
____mg 
 
 
 
 
3 
____mg 
 
 
 
 
4 
____mg 
 
 
 
 
5 
____mg 
i$ 
 
 
 
6 
____mg 
 
 
 
 
7 
____mg 
 
 
 
 
8 
____mg 
b, d, f* 
 
 
 
9 
____mg 
 
 
 
 
10 
____mg 
 
 
 
 
11 
____mg 
 
 
 
 
12 
____mg 
 
 
 
 
13 
____mg 
 
 
 
 
14 
____mg 
 
 
 
 
15 
____mg 
b, d, f* 
 
 
 
16 
____mg 
 
 
 
 
17 
____mg 
 
 
 
 
18 
____mg 
 
 
 
 
19 
____mg 
 
 
 
 
20 
____mg 
 
 
 
 
21 
____mg 
b, d, f* 
 
 
 
29 
Start next cycle on Day 29 or when blood count parameters are met (whichever occurs later). For end of therapy 
observations, see Section 7.1. 
@ Obtain weekly. If patient develops hematologic toxicity as defined in Section 5.2, CBCs should be checked every 3 to 4 days until recovery to Grade 3. 
*Obtain within 24 hours prior to starting each cycle and weekly during cycle 1. If menstrual cycles are known to be irregular, pregnancy testing must occur every 14 
days beginning with Day 1 of Cycle 2.  If a patient misses her period or menstrual bleeding becomes irregular, hold lenalidomide and perform pregnancy testing and 
counseling immediately.Only for females of childbearing potential.  
#Obtain prior to each odd-numbered cycle of therapy (ie, prior to cycles 3, 5, 7, 9, 11 and 13) for the first 13 cycles. During cycles 14-26, obtain every third cycle 
(ie, prior to cycles 16, 19, 22 and 25), after cycle 26 and as clinically indicated.  
^ Obtain at same time points as brain MRI, for patients with known or suspected spinal disease. 
$ For PK study, obtain 2 mL blood in heparinized tube (green top) any day between Days 5-21 of Cycle 1 and any day between Days 5-21 of the first cycle 
following a dose reduction at the time of safety lab monitoring. See Section 13.0 
See 
Section 
5.0 
for 
Dose 
Modifications 
for 
Toxicities. 
For 
COG 
Supportive 
Care 
Guidelines 
see: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp. 
 
 


 
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Page 28 
 
 
4.3.2 
Lenalidomide Cycle – Regimen B (High Dose: 115 mg/m2) 
Four consecutive weeks (28 days) will constitute one cycle (Lenalidomide daily x 21 
days followed by 7 day rest). This therapy delivery map relates to all cycles of Regimen 
B. Use a copy of this page once for each cycle. (Please note cycle number below.) 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Criteria to start this cycle$1&ȝ/DQGSODWHOHWFRXQWȝ/WUDQVIXVLRQLQGHSHQGHQWFRQILUPDWLRQRIQHJDWLYHSUHJQDQF\WHVW and the 
use of 2 methods of effective birth control for female patients of childbearing potential or commitment to complete abstinence, completion and 
documentation of required counseling. Details are in Section 4.0 (Treatment Overview). The Therapy Delivery Map for this cycle is on 1 page. 
DRUG 
ROUTE DOSAGE 
DAYS IMPORTANT NOTES 
OBSERVATIONS 
Lenalidomide 
NSC#703813 
 
PO 
115  
mg/m2/dose 
1-21 
See admin guidelines 
in Section 4.3. 
a. History, PE (Ht, Wt, VS), Performance Status 
b. CBC (differential, platelets) 
c. Urinalysis 
d. Electrolytes (inc BUN, Calcium, PO4, Magnesium)  
e. Creatinine; Total protein; Albumin, ALT, AST, bilirubin 
f. Pregnancy test (female pts of childbearing potential only) 
g. Brain MRI with and without gadolinium 
h. Spine MRI with and without gadolinium 
i.  Pharmacokinetic study (see Section 13.0) 
j.  Required Education and Counseling; Confirmation of birth 
control/abstinence  
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
Please Enter Cycle #: _____ 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Lenalidomide 
____mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
____mg 
a, b@, c, d, e, f*, g#, h^, j 
 
 
 
2 
____mg 
 
 
 
 
3 
____mg 
 
 
 
 
4 
____mg 
 
 
 
 
5 
____mg 
i$ 
 
 
 
6 
____mg 
 
 
 
 
7 
____mg 
 
 
 
 
8 
____mg 
b, d, f* 
 
 
 
9 
____mg 
 
 
 
 
10 
____mg 
 
 
 
 
11 
____mg 
 
 
 
 
12 
____mg 
 
 
 
 
13 
____mg 
 
 
 
 
14 
____mg 
 
 
 
 
15 
____mg 
b, d, f* 
 
 
 
16 
____mg 
 
 
 
 
17 
____mg 
 
 
 
 
18 
____mg 
 
 
 
 
19 
____mg 
 
 
 
 
20 
____mg 
 
 
 
 
21 
____mg 
b, d, f* 
 
 
 
29 
Start next cycle on Day 29 or when blood count parameters are met (whichever occurs later). For end of therapy 
observations, see Section 7.1. 
@ Obtain weekly. If patient develops hematologic toxicity as defined in Section 5.2, CBCs should be checked every 3 to 4 days until recovery to grade 3. 
*Obtain within 24 hours prior to starting each cycle and weekly during cycle 1. If menstrual cycles are known to be irregular, pregnancy testing must occur every 
14 days beginning with Day 1 of Cycle 2.  If a patient misses her period or menstrual bleeding becomes irregular, hold lenalidomide and perform pregnancy testing 
and counseling immediately. Only for females of childbearing potential.  
#Obtain prior to each odd-numbered cycle of therapy (ie, prior to cycles 3, 5, 7, 9, 11 and 13) for the first 13 cycles. During cycles 14-26, obtain every third cycle 
(ie, prior to cycles 16, 19, 22 and 25), after cycle 26 and as clinically indicated.  
^ Obtain at same time points as brain MRI, for patients with known or suspected spinal disease. 
$ For PK study, obtain 2 mL blood in heparinized tube (green top) any day between Days 5-21 of Cycle 1 and any day between Days 5-21 of the first cycle 
following a dose reduction at the time of safety lab monitoring. See Section 13.0. 
See 
Section 
5.0 
for 
Dose 
Modifications 
for 
Toxicities. 
For 
COG 
Supportive 
Care 
Guidelines 
see: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp. 


 
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Page 29 
 
 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
Lenalidomide dose reductions will not be re-escalated, even if there is minimal or no toxicity with 
the subsequent reduction in dose. Patients who experience significant toxicity (as listed in Sections 
5.1 and 5.2) will have the dose reduced by 25% on subsequent cycles. Two dose reductions are 
allowed, as long as there is no evidence of disease progression (see Section 10.0). Each dose 
reduction will be a reduction of 25% of the starting dose; therefore the first dose reduction will be 
to 75% of the starting dose (either to 15 mg/m2/dose for patients on Regimen A or to 86 mg/m2/dose 
for patients on Regimen B), and a second reduction will be to 50% of the starting dose (either to 
10 mg/m2/dose for patients on Regimen A or to 58 mg/m2/dose for patients on Regimen B).  See 
Appendix IX for Regimen A dosing tables. Patients who again experience dose modifying toxicity 
after two dose reductions will be taken off protocol therapy.  
 
If a dose reduction occurs, a blood sample for pharmacokinetic study should be drawn during the 
cycle subsequent to the reduction. See Section 13.0 for details of pharmacokinetic sample 
collection. 
 
5.1 
Non-Hematologic Toxicities  
The dose of lenalidomide will be reduced for any of the following toxicities at least 
possibly attributed to lenalidomide: 
• Any Grade 4 non-hematological toxicity  
• Any Grade 3 non-hematological toxicity with the specific exclusion of:  
 
- Grade 3 nausea and vomiting controlled by antiemetics   
 
- Grade 3 fever or infection  
- Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia 
responsive to oral supplementation. 
• Any Grade 2 non-hematologic toxicity that persists for > 3 days and is considered 
sufficiently medically significant or sufficiently intolerable by patients that it 
requires treatment interruption  
• Any other adverse event attributed to lenalidomide that requires treatment 
interruption for > 3 days or which recurs upon drug rechallenge and requires 
treatment interruption. 
• Non-hematological toxicity that causes a delay of t 14 days between treatment 
cycles. 
  
Patients who experience non-hematologic toxicity should have appropriate laboratory 
testing at least twice weekly (3-4 days apart) until the toxicity has resolved. 
 
Lenalidomide will be held for any patient experiencing any Grade hemorrhagic or bullous 
skin rash until a specific evaluation to exclude toxic epidermal necrolysis (TEN) has been 
performed.  Any patient with evidence of TEN or Stevens-Johnson syndrome will not be 
retreated with lenalidomide. 
 
If the patient experiences a thromboembolic event unrelated to a central line, 
lenalidomide will be discontinued and the patient will be taken off protocol therapy. 
 
5.2 
Hematologic Toxicities   
The dose of lenalidomide will be reduced for any of the following toxicities: 
• Grade 4 decreased neutrophil count (neutropenia) > 3 days duration 
• Grade 4 decreased platelet count (thrombocytopenia)  


 
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Page 30 
 
 
SODWHOHWWUDQVIXVLRQVSHUFycle for platelet counts < ȝL  
14 day delay in starting subsequent cycles due to low ANC (< 1,000ȝ/ or low 
platelet count (< 100,000/ȝL.  
• ,I$1&ȝ/ and platelets <100,000ȝ/ during the 21 day dosing period, the 
lenalodomide should be held until recovery. Counting of cycle days should 
continue uninterrupted. 
Patients who experience hematologic toxicity should have appropriate laboratory testing at 
least twice weekly (3-4 days apart) until the toxicity has resolved (i.e. ANC > 10ȝ/ and 
platelets >100,000/ȝL) . 
 
 
 
6.0 
DRUG INFORMATION 
6.1 
LENALIDOMIDE (RevlimidTM, CC-5013, CDC-501) NSC# 703813, IND # (05/15/18) 
 
Source and Pharmacology: Lenalidomide is a thalidomide analogue with the chemical 
name 
3-(4’-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl) 
-2,6-piperidinedione. 
The 
molecular weight of lenalidomide is 259.25.  
Lenalidomide is an immunomodulatory agent with a mechanism of action that remains to 
be fully characterized. Lenalidomide inhibits proliferation of certain hematopoietic tumor 
cells (including MM plasma tumor cells and those with deletions of chromosome 5), 
enhances T cell- and natural killer (NK) cell-mediated immunity and increases the number 
of NK T cells, inhibits angiogenesis by blocking the migration and adhesion of endothelial 
cells and the formation of microvessels, augments fetal hemoglobin production by CD34+ 
hematopoietic stem cells, and inhibits secretion of proinflammatory cytokines (eg, TNF-Į 
and IL-6) from monocytes. Lenalidomide also inhibited the expression of cycoloxygenase-
2 (COX-2) but not COX-1 in vitro. 
 
Following oral administration, lenalidomide is rapidly absorbed with maximum plasma 
concentrations occurring between 0.5 and 1.5 hours postdose. Co-administration with food 
does not alter the extent of lenalidomide absorption (area under the concentration time 
curve, AUC) but does reduce the maximal plasma concentration (Cmax) by 36%. The Cmax 
and AUC increase proportionally (linearly) with increases in dose and multiple dosing (up 
to 100 mg twice daily) does not cause a significant drug accumulation. In plasma, the 
relative exposures of the S- and R- enantiomers of lenalidomide are approximately 55% 
and 45%, respectively. 
 
Lenalidomide binding to plasma proteins is low with mean plasma protein binding around 
30% (22.7% and 29.2% in multiple myeloma patients and healthy volunteers, respectively). 
Lenalidomide is neither metabolized by nor inhibited or induced by the cytochrome P450 
pathway. In healthy volunteers, lenalidomide undergoes limited metabolism and the parent 
compound is the predominant circulating component. Approximately 65% to 85% of 
lenalidomide is eliminated unchanged in the urine. The half-life of elimination is 
approximately 3 hours at the clinically relevant doses and steady-state levels are achieved 
within 4 days. Pharmacokinetic analyses in patients with impaired renal function indicate 
that as renal function decreases, the total drug clearance decreases proportionally resulting 
in an increase in AUC. The half-life of lenalidomide increased from approximately 3.5 
hours in subjects with creatinine clearance > 50 mL/min to more than 9 hours in subjects 
with creatinine clearance < 50 mL/min; therefore, patients with inadequate renal function 
are ineligible for this study. 


 
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With regards to potential drug interactions, the periodic monitoring of digoxin plasma 
levels is recommended due to increased Cmax with concomitant administration of 
lenalidomide. Patients taking concomitant therapies such as erythropoietin stimulating 
agents or estrogen containing therapies may have an increased risk of venous 
thromboembolic events. Therefore, erythropoietic agents should not be used while patients 
are receiving lenalidomide on this trial. Other agents that may increase the risk of 
thrombosis, such as estrogen containing therapies, should be used with caution in patients 
receiving lenalidomide. 
 
Toxicity:  
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Lenalidomide (CC-5013, NSC 703813) 
 
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_applications/docs/aeguidelines.pd
f  for further clarification. Frequency is provided based on 4081 patients. Below is the 
CAEPR for Lenalidomide (CC-5013). 
 
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 2.7, March 14, 20181 
 
 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Blood and lymphatic system 
disorders - Other 
(pancytopenia) 
 
  
 
Febrile neutropenia 
 
  
 
Hemolysis 
 
  
CARDIAC DISORDERS 
  
 
 
Atrial fibrillation 
  
 
 
Heart failure 
  
 
 
Myocardial infarction2 
  
EAR AND LABYRINTH DISORDERS 
  
 
Vertigo 
 
  


 
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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
ENDOCRINE DISORDERS 
  
 
 
Hyperthyroidism 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 3) 
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Cataract 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
Constipation 
 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
  
 
Dyspepsia 
 
  
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 3) 
 
Generalized edema 
 
  
 
Non-cardiac chest pain 
 
  
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
 
 
Hepatobiliary disorders - Other 
(cholestasis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
 
 
Anaphylaxis 
  
 
 
Immune system disorders - Other 
(angioedema) 
  
 
 
Immune system disorders - Other 
(graft vs. host disease)3 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 Infection4 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
  
 
Fall 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
 
Blood bilirubin increased 
 
  
 
GGT increased 
 
  


 
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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Investigations - Other (C-
Reactive protein increased) 
 
  
 
 
Lipase increased 
  
 
Lymphocyte count decreased  
 Lymphocyte count decreased (Gr 4) 
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased  
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hyperglycemia 
 
  
 
Hyperuricemia 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hyponatremia 
 
  
 
Hypophosphatemia 
 
  
 
Iron overload 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
 
Bone pain 
 
  
 
Generalized muscle 
weakness 
 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
 
Pain in extremity 
 
  
 
 
Rhabdomyolysis5 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
 
Leukemia secondary to oncology 
chemotherapy6 
  
 
 
Myelodysplastic syndrome6 
  
 
 
Neoplasms benign, malignant 
and unspecified (incl cysts and 
polyps) - Other (tumor flare)7 
  
 
 
Neoplasms benign, malignant 
and unspecified (incl cysts and 
polyps) - Other (second primary 
malignancies) 
  
 
 
Treatment related secondary 
malignancy6 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Depressed level of 
consciousness 
 
  


 
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 Adverse Events with Possible  
 Relationship to Lenalidomide (CC-5013) 
 (CTCAE 5.0 Term) 
[n= 4081] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Dysesthesia 
 
  
 
Dysgeusia 
 
  
 
Headache 
 
  
 
Paresthesia 
 
  
 
Peripheral motor neuropathy  
  
 
Peripheral sensory 
neuropathy 
 
  
 
 
Stroke2 
  
 
Syncope 
 
  
 
Tremor 
 
  
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
 
Psychiatric disorders - Other 
(mood altered) 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
  
 
 
Erythema multiforme 
  
 
Hyperhidrosis 
 
 Hyperhidrosis (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction 
with eosinophilia and systemic 
symptoms [DRESS]) 
  
 
Skin and subcutaneous tissue 
disorders - Other (pyroderma 
gangrenosum) 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
SURGICAL AND MEDICAL PROCEDURES 
  
 
 
Surgical and medical procedures 
- Other (impaired stem cell 
mobilization)8 
  
VASCULAR DISORDERS 
  
 
Hematoma 
 
  
 
Hypertension 
 
  
 
Hypotension 
 
  
 
Peripheral ischemia 
 
  
 
Thromboembolic event9 
 
 Thromboembolic event9 (Gr 3) 
 
Vasculitis 
 
  


 
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1This 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. 
 
2Myocardial infarction and cerebrovascular accident (stroke) have been observed in multiple 
myeloma patients treated with lenalidomde and dexamethasone. 
 
3Graft vs. host disease has been observed in subjects who have received lenalidomide in the 
setting of allo-transplantation. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5The rare adverse event of rhabdomyolysis has been observed with lenalidomide. The reports of 
rhabdomyolysis were confounded by concurrent use of statins and dexamethasone, concurrent 
viral and bacterial infections, trauma, and serotonin syndrome. Statins, infections, trauma, and 
serotonin syndrome are known risk factors for rhabdomyolysis. 
 
6There has been an increased frequency of secondary malignancies (including ALL, AML, and 
MDS) in multiple myeloma patients being treated with melphalan, prednisone, and lenalidomide 
post bone marrow transplant. 
 
7Serious tumor flare reactions have been observed in patients with chronic lymphocytic leukemia 
(CLL) and lymphoma. 
 
8A decrease in the number of stem cells (CD34+ cells) collected from patients treated with >4 
cycles of lenalidomide has been reported. 
 
9Significantly increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), and 
arterial thrombosis has been observed in patients with multiple myeloma receiving lenalidomide 
with dexamethasone. 
 
10Gastrointestinal hemorrhage includes: Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
11Gastrointestinal obstruction includes:  Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and 
Small intestinal obstruction under the GASTROINTESTINAL DISORDERS SOC. 
 
12Osteonecrosis of the jaw has been seen with increased frequency when lenalidomide is used in 
combination with bevacizumab, docetaxel (Taxotere®), prednisone, and zolendronic acid 
(Zometa®). 
 
 
NOTE:  While not observed in human subjects, lenalidomide, a thalidomide analogue, caused 
limb abnormalities in a developmental monkey study similar to birth defects caused by 
thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or 
embryo-fetal death. Pregnancy must be excluded before start of treatment. Prevent pregnancy 
during treatment by the use of two reliable methods of contraception. 
 
 


 
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Adverse events reported on lenalidomide (CC-5013) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that lenalidomide (CC-5013) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (monocytosis); Disseminated intravascular coagulation; Eosinophilia 
CARDIAC DISORDERS - Atrial flutter; Atrioventricular block first degree; Cardiac arrest; Cardiac 
disorders - Other (cardiovascular edema); Cardiac disorders - Other (ECG abnormalities); Chest 
pain - cardiac; Left ventricular systolic dysfunction; Palpitations; Pericarditis; Sinus bradycardia; 
Sinus tachycardia; Supraventricular tachycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Cushingoid 
EYE DISORDERS - Dry eye; Flashing lights; Retinopathy 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal mucositis; Ascites; Colonic 
perforation; Dysphagia; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - 
Other (Crohn's disease aggravated); Gastrointestinal disorders - Other (diverticulitis); 
Gastrointestinal disorders - Other (pale feces); Gastrointestinal hemorrhage10; Gastrointestinal 
obstruction11; Ileus; Mucositis oral; Pancreatitis; Rectal mucositis; Small intestinal mucositis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Multi-organ 
failure 
HEPATOBILIARY DISORDERS - Cholecystitis 
INFECTIONS AND INFESTATIONS - Conjunctivitis; Infections and infestations - Other 
(opportunistic infection associated with >=Grade 2 Lymphopenia); Myelitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Hip fracture; Vascular 
access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Cholesterol high; Creatinine 
increased; Electrocardiogram QT corrected interval prolonged; INR increased; Investigations - 
Other (hemochromatosis) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypoglycemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; 
Joint effusion; Muscle weakness lower limb; Neck pain; Osteonecrosis of jaw12 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dysphasia; Edema cerebral; 
Encephalopathy; Intracranial hemorrhage; Ischemia cerebrovascular; Leukoencephalopathy; 
Memory impairment; Nervous system disorders - Other (hyporeflexia); Spinal cord compression; 
Seizure; Somnolence; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Psychosis 
RENAL AND URINARY DISORDERS - Urinary frequency; Urinary incontinence; Urinary tract 
pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast 
disorders - Other (hypogonadism); Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Allergic rhinitis; Atelectasis; Bronchopulmonary hemorrhage; Hypoxia; Laryngeal 
mucositis; Pharyngeal mucositis; Pleural effusion; Pulmonary hypertension; Respiratory failure; 
Tracheal mucositis; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Nail loss; Photosensitivity; Rash 
acneiform; Skin and subcutaneous tissue disorders - Other (Sweet’s Syndrome); Urticaria 
VASCULAR DISORDERS - Hot flashes; Phlebitis; Vascular disorders - Other (hemorrhage NOS) 
 
 
Note: Lenalidomide (CC-5013) 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. 
 


 
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Effect in Pregnancy and Lactation: 
Lenalidomide is Pregnancy category X. It can cause fetal harm when administered to a 
pregnant woman and is contraindicated in women who are or may become pregnant. There 
are no adequate and well-controlled studies in pregnant women. However, in an 
embryofetal developmental toxicity study in monkeys, teratogenicity, including 
thalidomide-like limb defects occurred in offspring when pregnant monkeys received oral 
lenalidomide during organogenesis at doses approximately 0.17 times the adult maximum 
recommended human dose (MRHD) of 25 mg, based on BSA. Similar studies in pregnant 
rabbits and rats at 20 times and 200 times the MRHD respectively, produced 
embryolethality in rabbits and no adverse reproductive effects in rats. In another study, 
pregnant rats received lenalidomide from organogenesis through lactation; some delay in 
sexual maturation occurred in male offspring. As with thalidomide, the rat model may not 
adequately address the full spectrum of potential human embryofetal developmental 
effects for lenalidomide.  
The requirements of this study and the requirements to receive the commercially available 
supply are slightly different.  For the purpose of this study, female of childbearing potential 
(FCBP) is a sexually mature (at least Tanner 2) female who: 1) has achieved menarche or 
breast development in Tanner Stage 2 or greater, and 2) has not undergone a hysterectomy 
or bilateral oophorectomy and must use effective means of contraception for 28 days before 
therapy, during lenalidomide therapy and dose interruptions, and for 28 days following 
discontinuation of lenalidomide therapy or continually abstain from reproductive 
heterosexual intercourse.  Venous thromboembolism (VTE) has been seen in patients with 
multiple myeloma receiving lenalidomide plus dexamethasone and patients with 
myelodysplastic syndrome receiving lenalidomide monotherapy (to a lesser extent).  
Because oral contraceptives may also place the patient at risk of VTE, physicians should 
discuss this increased risk and the risk/benefit of contraceptive methods with patients 
receiving lenalidomide. 
Male patients must agree to completely abstain from sexual contact with women who are 
pregnant or are able to become pregnant or use a latex condom every time he engages in 
sexual contact with women who are pregnant or who may become pregnant.   
 
If a pregnancy occurs during treatment, the drug must be immediately discontinued and the 
suspected fetal exposure should be reported to CTEP via CTEP-AERS. Refer to Section 
11.9. 
 
It is not known whether lenalidomide is excreted in human milk. Since many drugs are 
excreted in human milk and because of the potential for adverse reactions in nursing infants 
from lenalidomide, a decision should be made whether to discontinue nursing or to 
discontinue the drug, taking into consideration the importance of the drug to the mother. 
 
Formulation and Stability: 
Lenalidomide is available in 2.5 mg, 5 mg, and 25 mg capsules for oral administration for 
the purpose of this study. Lenalidomide 10 mg capsules will not be used in this study. 
 
Each capsule contains lenalidomide as the active ingredient and the following inactive 
ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. The capsules are supplied in tamper-evident, child-resistant, opaque, 


 
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high density polyethylene (HDPE) bottles) with polypropylene caps.  Each bottle contains 
100 capsules. Lenalidomide should be stored at 25°C (77°F); excursions permitted to 15-
30°C (59-86°F).  
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
Each subject must receive counseling regarding the use and risks of lenalidomide by a 
healthcare professional who has received specific training by Celgene.  Additional 
information about the training of these healthcare professionals can be found in Section 
3.1.5.1 and Appendix I.  The counseling of each subject must be documented using the 
Lenalidomide Education and Counseling Guidance Document (Appendix III).  Once 
documentation has been confirmed, a pharmacist may dispense the investigational 
lenalidomide to the patient.  Pharmacists may only dispense up to a 28-day supply at one 
time (1 cycle, or a 21-day supply for the purpose of this study).  A Lenalidomide 
information sheet (Appendix V) must be provided each and every time the medication is 
dispensed.  Prescriptions may not be mailed to the patient.   
 
Lenalidomide capsules should not be opened or crushed. If lenalidomide powder contacts 
the skin, it must be washed immediately and thoroughly with soap and water. If 
lenalidomide contacts mucous membranes, flush thoroughly with water.  
 
Lenalidomide should be taken by mouth with a full glass of water and without food at 
approximately the same time each day for 21 consecutive days. If nausea occurs after 
taking the dose, administer with food as this may decrease nausea.  If a dose is forgotten 
but remembered within 8 hours, the missed dose should be taken/given immediately. If 
more than 8 hours have passed since the time the dose was due, that day’s dose should be 
skipped.  If a dose is vomited within 10 minutes of taking the dose and the capsules are 
visible in the emesis, the dose should be repeated and the patient’s provider should be 
notified.  
 
Procedures for the proper handling and disposal of hazardous/anticancer drugs should be 
considered. 
 
Supplier:  Supplied by Celgene and distributed by the NCI DTCD. Do not use 
commercially available drug. 
 
Agent Ordering 
NCI supplied agent may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained.)  The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), 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 
investigator at that institution. One additional dose of lenalidomide may be ordered and 
dispensed so it is readily available in the event the patient vomits the capsules. 
 


 
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Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees must submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx 
>.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance 
of an “active” account status and a “current” password.   For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See the 
CTEP 
home 
page 
at 
http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs 
for 
the 
Procedures 
for 
Drug 
Accountability 
and 
Storage 
and 
http://ctep.cancer.gov/forms/default.htm to obtain a copy of the DARF and Clinical Drug 
Request form.) 
 
Agent Returns 
Investigators/Designees must return unused DCTD supplied investigational agent to the 
NCI clinical repository as soon as possible when: the agent is no longer required because 
the study is completed or discontinued and the agent cannot be transferred to another 
DCTD sponsored protocol; the agent is outdated or the agent is damaged or unfit for use. 
Regulations require that all agents received from the DCTD, NCI be returned to the DCTD, 
NCI for accountability and disposition. Return only unused vials/bottles. Do NOT return 
opened or partially used vials/bottles unless specifically requested otherwise in the 
protocol. See the CTEP web site for Policy and Guidelines for Investigational agent 
Returns at: http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs. The 
appropriate forms may be obtained at: http://ctep.cancer.gov/forms/default.htm. 


 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 (except where explicitly 
prohibited within the protocol). 
 
7.1 
Required Clinical, Laboratory and Disease Evaluations  
All baseline studies must be performed prior to starting protocol therapy unless otherwise 
indicated below. Obtain other studies prior to start of subsequent cycles and as 
otherwise indicated.   
STUDIES TO BE OBTAINED 
Baseline 
Prior to 
Each 
Cycle 
During 
Each 
Cycle 
When Patient 
is Removed 
from Protocol 
Therapy 
History 
X 
X 
 
 
Physical Exam (Ht, Wt, VS) 
X 
X 
 
X 
Performance Status 
X 
X 
 
X 
CBC (differential, platelets) 
X 
X 
WeeklyA 
X 
Urinalysis 
X 
X 
 
X 
Electrolytes (including BUN, Calcium, PO4, 
Magnesium)  
X 
X 
Weekly 
X 
Creatinine 
X 
X 
 
 
Total protein, AST, ALT, albumin, bilirubin 
X 
X 
 
X 
Pregnancy test (serum or urine, with 
sensitivity of 25 mIU/mL)  (for females of 
childbearing potential) 
XB 
XB 
WeeklyC 
XD 
Confirmation of use of 2 effective methods 
of  birth control OR confirmation of 
complete abstinence (for female patients of 
childbearing potential) 
X 
X 
 
 
Education and Counseling (all patients)E  
 
X 
 
X 
Brain MRI with and without gadolinium 
X F 
XG 
 
X 
Spine MRI with and without gadoliniumF,H 
X 
XG 
 
X 
Pharmacokinetic studies (see Section 13.0) 
 
 
XI 
 
A If patient develops hematologic toxicity as defined in Section 5.2, CBCs should be checked every 
3 to 4 days until recovery. 
B Obtain 2 weeks prior to study enrollment and again within 24 hours prior to Day 1 of each cycle. 
C Obtain weekly during cycle 1. Females with irregular menstruation must have a pregnancy test 
every 14 days while receiving protocol therapy (including breaks in treatment). Pregnancy test is 
also required if patient misses her period or has unusual menstrual bleeding. 
D Pregnancy testing must also occur at Day 28 (and at Day 14 if female has irregular menstruation) 
after lenalidomide discontinuation). 
E The Lenalidomide Education and Counseling Document (Appendix III) must be completed and 
signed by a trained counselor at the site prior to each dispensing of lenalidomide. 
F Obtain brain MRI within 1 week prior to study enrollment. Spine MRI (if necessary) may be 
obtained within 2 weeks prior to enrollment. 
G Obtain prior to each odd-numbered cycle of therapy (ie, prior to cycles 3, 5, 7, 9, 11 and 13) for 
the first 13 cycles. During cycles 14-26, imaging will be performed every third cycle (ie, prior to 


 
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16, 19, 22 and 25), after cycle 26, and as clinically indicated. See Section 14.0 for imaging 
requirements. 
H Obtain in patients with a history of spinal or leptomeningeal disease, or those patients with 
symptoms suspicious of spinal disease. Obtain spine MRI at same time points as brain MRI. 
I PK blood sample must be obtained prior to the daily dose between Day 5-21 of cycle 1 at the time 
of routine safety lab monitoring. In the event of a dose reduction, a blood sample must also be 
obtained between Day 5-21 of the cycle following the dose reduction. 
This table only includes evaluations necessary to answer the primary and secondary 
aims. Obtain other studies as indicated for good clinical care.  
 
7.2 
Follow-up  
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. This includes required pregnancy testing for all female patients of childbearing 
potential on Day 28 following the last dose of lenalidomide. Patients with irregular 
menstrual cycles must have pregnancy testing completed on Day 14 and Day 28 following 
the last dose of lenalidomide.  
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
8.1 
Criteria for Removal from Protocol Therapy 
a) 
Progressive disease (see definition in Section 10.0). 
b) 
Significant toxicity at least possibly attributed to lenalidomide despite two dose 
reductions (as stated in Section 5.0). 
c) 
Refusal of further protocol therapy by patient/parent/guardian. 
d) 
Completion of 26 cycles of protocol therapy. 
e) 
Physician determines it is in patient’s best interest. 
f) 
Development of a second malignancy. 
g) 
Patient becomes pregnant while on study. 
h) 
Refusal to cooperate with required birth control methods or to commit to complete  
 
abstinence. 
i) 
Development of a thromboembolism, unrelated to central line. 
j) 
Evidence of toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Follow-up data will be required unless consent was withdrawn. 
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent. 


 
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d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Sample Size and Study Duration 
Approximately 45 patients per year less than 10 years of age with progressive/recurrent 
and high-risk LGA were enrolled on COG-A9952, Chemotherapy for Progressive Low 
Grade Astrocytoma in Children Less Than Ten Years Old. About half of these children (22 
patients) would be expected to progress and would be eligible for the current study.  
 
The total accrual of newly diagnosed LGA patients on CCG-9891/POG-9130, Treatment 
of Newly Diagnosed Low Grade Astrocytomas, was 713 over a period of 5 years. About 
40% of these patients were older than 10 years of age and 20% progressed within 6 years 
of diagnosis. This corresponds to about 11 patients per year older than 10 years with 
progressive LGA. Adding to this those who will be entered because of symptomatic, 
incomplete resections, we would expect approximately 20 patients per year older than 10 
years of age.  
 
Adding together patients who are younger than and those older than 10 years of age (22 + 
20 = 42), and taking into account patients who may opt for other treatments and the 
eligibility criteria of at least 1 prior therapy including carboplatin, we expect a total of 30 
patients with recurrent or progressive low-grade glioma per year. 
 
This study will enroll only patients with pilocytic astrocytoma and progressive optic 
pathway gliomas.  Based on prior COG enrollment, we estimate 70% of low grade glioma 
patients to be in this subset (30*0.7=21/yr).  The total accrual target for this study is 74 
patients enrolled in 3.5 years. Considering that some patients enrolled may be found to be 
ineligible, the maximum number of patients expected to be accrued is 80 patients.   
 
9.2 
Study Design 
This is a randomized study to estimate the response rate of children with recurrent or 
progressive pilocytic astrocytoma and optic pathway gliomas who are treated with 
lenalidomide assigned to either Regimen A low dose (20 mg/m2/dose) or Regimen B high 
dose (115 mg/m2/dose). 
 
9.3 
Methods of Analysis 
9.3.1 
Endpoints 
 
9.3.1.1 Primary Endpoint 
x 
Objective response – best response determined from the sequence 
of the objective statuses described in Section 10.0 ‘Response 
Criteria.’ 
9.3.1.2 Secondary Endpoints 
x 
Time to treatment failure (Event-free survival, EFS) – the time 
from study enrollment to tumor progression, tumor recurrence, 
death from any cause, or occurrence of a second malignant 
neoplasm. 


 
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x 
Time to death (Overall survival, OS) – the time from study 
enrollment to death from any cause. 
 
9.4 
Analysis of Efficacy 
A total of 74 eligible patients will be enrolled on this trial. Patients will be randomly 
assigned to either the low dose (Regimen A) or the high dose arm (Regimen B).  Each 
patient will be classified according to their ‘best response’ for the purposes of analysis of 
treatment effect. Best response is determined from the sequence of the objective statuses 
described in Section 10.0 ‘Response Criteria.’ A responder is defined as a patient who 
achieves a best overall response of CR or PR at any time on the study. If a patient achieves 
a PR or CR and later has progressive disease or relapse, then the patient will be counted as 
a responder. The response rate will be calculated as the ratio of the number of patients who 
demonstrate response (CR or PR) divided by the number of patients evaluable for response. 
The 95% confidence bounds for response rate are shown in the table below for several 
different outcomes. The computation is based on the binomial distribution, assuming the 
availability of 30 evaluable patients (7 inevaluable patients) for response in each arm (each 
dose level). All patients eligible for study who receive any study drug will be considered 
evaluable for response. Any patient who goes off protocol therapy for any reason 
(patient/parent/physician choice, adverse event profile, etc.) prior to the first response 
evaluation will be considered a non-responder. For example, an observed response rate of 
33% (10/30) will be consistent with the view that 17% or more patients will respond to the 
treatment. 
 
Outcome (#Response/#Patients) 95% Exact Confidence Bound on 
Response Rate 
20/30 
(0.47, 0.83) 
15/30 
(0.31, 0.69) 
10/30 
(0.17, 0.53) 
5/30 
(0.06, 0.35) 
 
There would be modest power to compare the response rates for the 2 dose cohorts.  With 
74 patients, we would have 80% power to detect a response rate difference of 35% vs. 15%, 
at the 1-sided 20% significance level. 
 
Disease progression will be based on the results of institutional review. Standard survival 
methods will be used for analysis of EFS and OS. Analyses include log rank tests and the 
product-limit (Kaplan-Meier) estimate for estimation of EFS and OS probability. 
Comparison of EFS between the two dose levels will primarily be exploratory.  With 74 
patients, we will have only approximately 69% power to detect a 15% increase in long-
term EFS (30% to 45%) with 50% patients receiving high dose vs. 50% receiving low dose, 
based on a one-sided logrank test with 20% Type I error rate.  
 
9.5 
Monitoring for Efficacy 
Patients will be randomly assigned to either the low dose or the high dose treatment.  Of 
the 37 patients on each treatment, we will closely monitor the first 20 patients enrolled. For 
each regimen, the early stopping criterion and the decision regarding ultimate further 
interest in this agent will be based on the number of objective responses and disease 
progressions in the first 6 months of treatment. If the early stopping rule is met for one 
treatment, that particular arm will be closed and the other arm will continue as planned. 
 


 
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A true response rate of 5% and a true early (6-month) progression rate of 40% are 
considered inadequate, whereas a true response rate of 20% and a true early (6-month) 
progression rate of 25% would be sufficient for further interest in this agent. 
 
The study will be a 2-stage design, with 20 evaluable patients in the first stage and 17 
evaluable patients in the second stage (37 patients total per treatment regimen), with 
decisions made as follows:   
 
Number of Evaluable 
Patients Enrolled 
Results 
Decision 
Stage I: 20 evaluable 
patients 
Zero or one responders or 10 
or more with early 
progression 
Terminate enrollment with the 
conclusion the regimen does 
not demonstrate sufficient 
disease control 
All other configurations of 
response or early progression 
Continue to the next stage and 
enroll 17 more patients 
Stage II:  17 additional 
evaluable patients (Total 
of 37: 20 from Stage I 
and 17 from Stage II) 
Cumulatively 3 or fewer 
responders or 15 or more with 
early progression 
Conclude the regimen does not 
demonstrate sufficient disease 
control 
All other configurations of 
response or early progression 
Conclude the regimen 
demonstrates sufficient disease 
control for further investigation 
 
 
A summary of the operating characteristics of this design are provided below: 
 
Response 
Probability 
Early 
Progression 
Probability 
Probability of 
Stopping at 
First Stage 
Probability 
Accept 
Regimen 
0.05 
0.40 
0.78 
0.05 
0.10 
0.40 
0.51 
0.24 
0.20 
0.30 
0.11 
0.81 
0.15 
0.25 
0.18 
0.73 
0.20 
0.25 
0.08 
0.88 
 
9.6 
Monitoring for Toxicity  
“Toxic events” will be defined as one in which a patient has two dose reductions and then 
experiences another significant toxicity as defined in Section 5.0, irrespective of 
attribution. A two-stage stopping rule will be used to monitor for an excessive number of 
these toxic events. All patients described below must be evaluable for toxicity.  All patients 
who receive at least one dose of lenalidomide will be evaluable for toxicity.  A review of 
treatment feasibility and patient safety will be undertaken if we observe at least 5/18 or 
8/36 toxic events.  The rule will be met about 4% of the time if the true incidence of toxic 
event is 10%, and 90% of the time if the true incidence is 30%. 
 
9.7 
Interim Monitoring of Toxic Death 
Toxic death is death predominantly attributable to treatment-related causes. The occurrence 


 
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of toxic death at any time will be a primary endpoint for safety monitoring. Any toxic death 
on study will be reviewed with CTEP and the DMSC prior to continuing enrollment on 
study.  The study will be stopped if there are two toxic deaths on study.  
 
9.8 
Analysis of Toxicity 
Estimates will be obtained using life-table methods, with an event defined as the first 
occurrence of a primary toxicity. Time scale used in the time to first occurrence of a key 
acute and subacute toxicity is time in days since the start of therapy. Patients who have 
progression or recurrence of disease will be censored in these analyses. The rates of 
individual toxicities in each course of treatment, the number of patients who require a dose 
reduction and number of patients who come off protocol therapy due to toxicity will be 
summarized using standard descriptive statistical methods. To evaluate hematologic 
toxicity of long term lenalidomide administration adverse event data will be collected 
using CTCAE version 4 toxicity coding. Grade 3 or greater hematologic toxicities will be 
recorded per reporting period and compared between 2 lenalidomide doses 
 
9.9 
Analysis of Lenalidomide Pharmacokinetic Parameters 
Correlation of lenalidomide concentration obtained from the steady-state sample and the 
number of cycles received prior to the occurrence of disease progression will be performed 
using Pearson’s correlation coefficient. Cox regression analysis will be used to assess the 
association between outcome and steady state levels at a particular cycle. 
 
9.10 
Analysis of Standard MR Sequences 
To compare the methods of MRI sequence, the response categories (complete response, 
partial response, stable disease, and progression) will be determined from the following 
three standard MR sequences, T2-weighted, FLAIR, T1-weighted post-contrast.  Percent 
agreement between the sequences will be estimated as the number of follow-up scans in 
which the corresponding sequence agreed divided by the total number of follow-up scans.  
Standard error will be estimated by use of the bootstrap method28 to account for the 
correlated dependent response data, and these values will be used to estimate the 95% 
confidence intervals.  The event-free survival distributions will be compared across the MR 
sequences, with a proportional hazards model developed for dependent survival data by 
Wei et al (1989).29 
 
9.11 
Effect of the Stratification on Response Rate 
At enrollment, the number of prior therapies, classified as 2 or fewer versus more than 2 
will be required to complete the treatment assignment process.  The efficacy rule described 
in Section 9.5 will be executed as written regardless of the number of prior therapies that a 
patient has received.  The risk for EFS-event and death associated with receiving more than 
2 prior regimens will be assessed using the stratified 1-sided log-rank test, with randomized 
regimen as the stratification factor.  Only patients enrolled after approval of the proposed 
amendment will be considered in the analysis.  If the resulting p-value is not significant at 
the 0.10 level or less, the EFS and OS results will be presented without regard to 
stratification factor. 
 
The following logistic regression model will be utilized: 
 


 
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'
'
1
2
3
e
Pr
|
;
1 e
:
1
1
0
i
i
x
i
x
i
i
i
CR or PR x
where x is
x
is the randomtreatment assignment
x
is
if the patient received three or more prior regimens and
otherwise
E
E
 

 
 
The value and p-value associated with the HVWLPDWHRIȕ3 will be used to infer whether there 
evidence of an association between response rate and number of prior regimens 
 
9.12 
Gender and Minority Accrual Estimates  
Both males and females of all races and ethnic groups are eligible for this study. The gender 
and minority distribution of the study population is expected to be: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
1 
3 
Not Hispanic or Latino 
37 
40 
77 
Ethnic Category: Total of all subjects 
39 
41 
80 
Racial Category 
 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
1 
1 
2 
Black or African American 
4 
3 
7 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
32 
36 
68 
Racial Category: Total of all subjects 
39 
41 
80 
 
This distribution was derived from CCG 9891/POG 9130. 
 
 
10.0 
EVALUATION CRITERIA 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 4.0 can be downloaded 
from 
the 
CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE 
v4.0 as referenced on the CTEP website (ie, v4.02 and all subsequent iterations prior to 
version 5.0). 
 
10.2 
Methodology to Determine Tumor Measurement  
Tumor dimensions are determined by measurement of the longest tumor dimension and its 
perpendicular for each target lesion. Regarding MRI imaging, the radiologist at each 
institution may select whatever sequence best highlights the tumor (T1 enhanced or T2 


 
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weighted or FLAIR images) and the same sequence should be used for serial measurements. 
Response determination will be based on a comparison of an area (W x T – see below) between 
the baseline assessment and the study date designated in the follow-up Report Form.  Reports 
for the follow-up exams should reiterate the measurements obtained at baseline for each target 
lesion.  Non-target lesions or newly occurring lesions should also be enumerated in these 
reports, and changes in non-target lesions should be described. 
 
Tumor response criteria are determined by changes in size using the longest tumor 
dimension, and its perpendicular. Either T1 or T2 weighted images are used - which ever 
gives the best estimate of tumor size. The following section describes the methodology. 
(See Figure 10.1 below for illustration) 
 
1. For MRI imaging (preferred), the longest diameter can be measured from the axial 
plane or the plane in which the tumor is best seen or measured, provided the same plane 
is used in follow ups. This longest measurement of the tumor is referred to as the width 
(W). Longest diameter of target lesion(s) should be selected in the axial plane only for 
CT. 
2. The perpendicular measurements should be determined - transverse (T) measurement, 
perpendicular to the width in the selected plane.  
3. The cystic or necrotic components of a tumor are not considered in tumor 
measurements. Therefore only the solid component of cystic/necrotic tumors should 
be measured. If cysts/necrosis composes the majority of the lesion, the lesion may not 
be “measurable”.   
Options: 
 
- 
if the cyst/necrosis is eccentric, the W and T of the solid portion should be 
measured, the cyst/necrosis excluded from measurement 
- 
if the cyst/necrosis is central but represents a small portion of the tumor (< 
25%), disregard and measure the whole lesion 
- if the cyst/necrosis is central but represents a large portion of the tumor, 
identify a solid aspect of the mass that can be reproducibly measured 
4. Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be 
measured accurately. Presence and location of leptomeningeal tumor spread should be 
noted and change in extent/thickness assessed on follow up studies.  
 
 
 


 
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Figure 10.1: COG Guidelines for Measurement of Tumor Size 
 
5. Overall Response Assessment 
The overall response assessment takes into account response in both the target and non-
target lesion, and the appearance of new lesions, 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, and new lesions in 
the preceding columns. 
 
 
Target Lesions 
 
Non-target Lesions 
 
New Lesions 
 
Overall Response 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR  
PR 
 CR, IR/SD 
No 
PR 
SD  
 CR, IR/SD 
No 
SD  
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
CR – Complete Response 
 
 
PR – Partial Response 
 
 
SD – Stable Disease 
PD – Progressive Disease 
IR – Incomplete Response 
 
The sections that follow discuss the selection and evaluation of each of these types 
of lesions. 
 
 
Z
AXIS
W
T
A
B
C
D
E
COG GUIDELINE: TUMOR SIZE
MEASUREMENT BASED ON
CROSS-SECTIONAL IMAGING
• A, B, C, D, & E are contiguous
parallel slices in the X-Y plane
(usually axial) showing the tumor
• W and T are the maximal
perpendicular diameters on the slice
(C in this example) showing the
largest surface area
• Tumor length in the Z-axis (L)
(perpendicular to X-Y plane) can be
obtained either by the [a] (difference
in table position of the first and last
slices showing the tumor + one slice
thickness), or [b] the product of (slice
thickness + gap) and the number of
slices showing the tumor
X-Y
PLANE
L


 
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10.3 
Selection of Target and Non-Target Lesions 
1. 
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.  
2. 
If multiple measurable lesions are present, up to 3 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 (including CSF positive for tumor cells).   
3. 
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). 
4. 
Any change in size of non-target lesions should be noted, though does not need to 
be measured. 
 
10.4 
Response Criteria for Target Lesions 
1. Response criteria are assessed in 2 dimensions – the product of W x T.  
2. To assess response/progression, the ratio is calculated: 
 
 
 
W x T (current scan)  
 
 
 
W x T (reference scan) 
 
3. 
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. 
 
4. For purposes of this study, response criteria for target lesions are: 
 
Complete Response (CR): Complete disappearance of all known disease for at least 4 
weeks. Complete response is dated from the time all lesions have disappeared.  
 
Partial response (PR): A reduction of at least 50% in the size of all measurable tumor as 
quantitated by the sum of the products of the largest diameters of measurable lesions and 
maintained for at least 4 weeks. Partial response is dated from the time of first observation. 
In addition, there can be no appearance of new lesions or progression of any lesion. 
 
Stable Disease (SD): A decrease of <50% or an increase of <25% in the sum of the 
products of the largest diameters of measurable lesions and no evidence of new lesions. 
 
Progressive Disease (PD):   LQFUHDVH LQ WKH sum of the products of the largest 
diameters of the measurable lesions or the appearance of one or more new lesions. Two-
dimensional measurements (using WHO criteria) of an existing tumor will be compared to 
the study baseline or best response scan (whichever is smaller) compared side-by-side. 
 
Local progression is defined as progression of known residual tumor or the appearance of 
tumor at known prior sites of disease that were at some point without evidence of disease. 
Distant progression is defined as the appearance of tumor at sites other than known prior 
sites of disease. Distant progression most often occurs in the subarachnoid space and may 
occur at any point within the neuraxis. Although rare, extra-CNS metastasis represents 
distant failure. Combined local and distant progression is defined when evaluation of the 
entire neuraxis reveals local and distant progression. 
 


 
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10.5 
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.  
 
10.6 
Retrospective Response Review 
MRI imaging for all patients on study will undergo retrospective central review following 
the completion of treatment. See Section 14.4 for imaging central review requirements. 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
11.1 
Purpose 
Adverse event (AE) 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. Certain adverse events must be 
reported in an expedited manner to allow for timelier monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI 
requires that AEs be submitted according to the timeframes in the AE reporting table 
assigned to the protocol, using the NCI’s Adverse Event Expedited Reporting System 
(CTEP-AERS). 
 
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 
KRVSLWDOL]DWLRQIRU 24 hours). This does not include hospitalizations which 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. 
7)  Pregnancy (See Section 11.9) 
 


 
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11.3 
Specific Examples for Expedited Reporting  
11.3.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 
possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting table in this protocol.  
 
11.3.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disrubtion of 
the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it occurs at 
any time following treatment with an agent under a NCI IND/IDE since these are 
considered serious AEs. 
 
11.3.3 Death 
Reportable Categories of Death  
 
x 
Death attributable to a CTCAE term.  
x 
Death Neonatal: A disorder characterized by cessation of life 
during the first 28 days of life.  
x 
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 CTCAE term associated with Grade 
5.  
x 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5.  
x Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “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 occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.3.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (eg, treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
The NCI 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:  


 
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x 
Leukemia secondary to oncology chemotherapy  
x 
Myelodysplastic syndrome  
x 
Treatment related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) 
must also be reported via the routine reporting mechanisms outlined in this 
protocol. 
 
11.3.4 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. 
 
11.3.5 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: 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(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.3.5.1 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 is known. If the baby 
is born with a birth defect or anomaly, then a second CTEP-AERS report 
is required. 
 
11.3.5.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any 
Pregnancy loss should 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. 
 
11.3.5.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring 
during the first 28 days of birth”, should be reported expeditiously, as 
Grade 4 “Death neonatal” under the “General disorders and 
administration” SOC when the death is the result of a patient 
pregnancy or pregnancy in partners of men on study. Do NOT report 
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partners of men on study as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
11.4 
Reporting Requirements for Specialized AEs  
11.4.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (eg, elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
a. 
If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. 
If the AE resolves and then recurs, the investigator must re-assess the event 
to determine if an expedited report is required. 
c. 
No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.4.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
11.4.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.5 
Exceptions to Expedited Reporting 
11.5.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and 
Potential Risks (CAEPR) that contains a list of events that are considered expected 
for CTEP-AERS reporting purposes. (Formerly referred to as the Agent Specific 
Adverse Event List (ASAEL).)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to the 
NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in 
parentheses after the event. If the CAEPR is part of a combination IND using 
multiple investigational agents and has an SAE listed on different SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
 


 
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11.5.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under the 
CTEP-AERS reporting table for this protocol. 
 
11.6 
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.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database.   
 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 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 website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted 
electronically 
to 
NCI 
via 
CTEP-AERS 
at: 
https://eapps-
ctep.nci.nih.gov/ctepaers 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to 301-897-
7497.  
 
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site.   
 
x 
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 event, 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 the investigator learning of the event.  
 
x 
Any event that results in a persistent or significant incapacity/substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth defect, 
or is an IME, which based upon the medical judgment of the investigator may 
jeopardize the patient and require intervention to prevent a serious AE, must be 
reported via CTEP-AERS if the event occurs following investigational agent 
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x 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 
hours.  
x 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE 
requires expedited reporting within 24 hours.  
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 
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 strongly recommended 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: 301-230-0159 (back-up: 301-897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax# 626-303-
1768; 
email: 
COGAERS@childrensoncologygroup.org; 
Attention: 
COG 
AERS 
Coordinator).  
 
x 
ALWAYS include the ticket number on all faxed documents. 
 
x 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
11.8 
Reporting Table for Late Phase 2 and Phase 3 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 
 
 


 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) 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) $Q\$(WKDWUHVXOWVLQLQSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQIRU 24 hours. This 
 
does not include hospitalizations which 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 serious when, based upon medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 
CFR 312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below.   
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
KUV 
 
7 Calendar Days 
 
 
24-Hour Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
KUV 
 
Not Required 
 
7 Calendar Days 
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. Additional Special Situations as 
Exceptions to Expedited Reporting are listed below (see Section 11.10).  
 
Expedited AE reporting timelines are defined as:  
“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 notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of 
learning of the AE.  
 
1SAEs 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:  
x 
All Grade 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x 
Grade 3 adverse events  
 
 
11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
x 
Grades 14 myelosuppression do not require expedited reporting unless 
unexpected.  
x 
Grades 13 of the following do not require expedited reporting: nausea, diarrhea, 
constipation, headache, rash and muscle cramps. 
x 
Expedited reporting guidelines for occurrence of pregnancy or suspected pregnancy 


 
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Pregnancy 
Females of Childbearing Potential: 
 
x 
Pregnancies and suspected pregnancies (including a positive pregnancy 
test regardless of age or disease state) of a female subject or the partner of 
a male subject occurring while the subject is on lenalidomide or within 28 
days after the subject’s last dose, are considered immediately reportable 
events. Lenalidomide must be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported via 
CTEP-AERS as a grade 4 event under: SOC pregnancy, puerperium and 
perinatal conditions; adverse event: pregnancy, puerperium and 
perinatal conditions-other, fetal exposure. 
o The female subject should be referred to an obstetrician-
gynecologist, preferably one experienced in reproductive toxicity 
for further evaluation and counseling. 
x 
The Investigator will follow the female subject until completion of the 
pregnancy, and must make an amendment to the initial pregnancy report 
immediately regarding the outcome of the pregnancy and neonatal status 
(either normal or abnormal outcome). 
x 
If the outcome of the pregnancy was abnormal (including spontaneous or 
therapeutic abortion, fetal demise and congenital abnormalities), the 
Investigator should report the abnormal outcome as an amendment to the 
initial pregnancy report as soon as the as the Investigator has knowledge 
of the outcome.  
x 
All neonatal deaths and neonatal complications that occur within 28 days 
of birth should be reported, without regard to causality, as an amendment 
to the initial pregnancy report. In addition, any infant death after 28 days 
that the Investigator suspects is related to the in utero exposure to the 
lenalidomide should also be reported as an amendment within 24 hours of 
the Investigator’s knowledge of the event. 
 
Male Subjects 
x 
If a female partner of a male subject taking investigational product 
becomes pregnant, the male subject taking lenalidomide should notify the 
Investigator, and the pregnant female partner should be advised to call her 
healthcare provider immediately. 
 
11.10 Routine Reporting of Adverse Events 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all CTEP-AERS 
reportable events and Grade 3 and higher Adverse Events. 
 
 


 
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12.0 
STUDY REPORTING AND MONITORING  
The Case Report Forms and the submission schedule are posted on the COG web site with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (eg, termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified 
in the protocol document. 
 
12.3 
CRADA/CTA 
NCI/ DCTD Standard Language to Be Incorporated into All Protocols Involving 
Agent(s) Covered by a Clinical Trials Agreement (CTA), a Cooperative Research and 
Development Agreement (CRADA) or a Clinical Supply Agreement, hereinafter referred 
to as Collaborative 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” 
(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: 
 
1. 
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 Agents contain confidential information and should 
not be shared or distributed without the permission of the NCI. If a copy of this 


 
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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. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other 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 
NCI, 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 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 Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available 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 
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 by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies 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 


 
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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. 
 
 
13.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS  
13.1 
Steady State Pharmacokinetic Study 
Participation in the pharmacokinetic study is required. Peripheral blood will be 
collected from all patients, for correlation of steady state pharmacokinetic levels of 
lenalidomide with best response and EFS at the patient dose.  
 
Serum samples will be assayed for lenalidomide by a validated high performance liquid 
chromatography assay with MS detection that has been developed for the quantitative 
determination of lenalidomide in biological matrices30. 
 
13.1.1 Sampling Schedule 
Plasma samples will be obtained prior to drug administration at the following three 
time-points: 
x 
any day between Days 5-21 on Cycle 1, 
x 
any day between Days 5-21 on the cycle following a first dose 
reduction 
x 
any day between Days 5-21 on the cycle following a second dose 
reduction. 
 
Patients do not need to be NPO for the samples. Whenever possible, institutions 
are encouraged to collect samples at the same time other labs are collected (eg, 
weekly CBC).  
 
13.1.2 Sample Collection and Processing Instructions 
Draw 2 mL of blood into a green top (sodium heparin) tube for pharmacokinetic 
evaluation, and immediately place on wet ice. Centrifuge whole blood at room 
temperature within 30 minutes to 1 hour at 2000G X 5 minutes. Transfer serum to 
individually labeled tubes and store at -70° C to -80° C.  
 
Label all serum specimens and the accompanying paperwork with the patient’s 
COG ID number, patient’s BPC number, the specimen collection date and time, 
the designated time point that the sample represents (eg, Cycle 1, Day X) and the 
COG study number (ACNS1022).  
 


 
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13.1.3 Sample Handling and Shipping Instructions  
Sample kits and shipping containers are not provided. 
Sample shipments should be made Monday through Thursday only, for delivery 
Tuesday through Friday. Weekend deliveries should be avoided. Sites should call 
Dr. Brigitte Widemann’s Laboratory (details below) to notify her of the shipment 
and provide the courier and tracking number. Ship all serum specimens on dry ice, 
with a completed ACNS1022 Pharmacokinetic Sample Collection Form for each 
sample shipment (see Appendix VII) to: 
 
Widemann Laboratory 
Pediatric Oncology Branch, NCI, CCR 
10 Center Dr. 10-CRC, Rm 1-5750 MSC 1101 
Bethesda, MD 20892-1928   
Phone: 301-496-7387 
 
   
14.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 (except where explicitly 
prohibited within the protocol). 
 
14.1 
Timing of MRIs 
To document the degree of residual tumor, standard whole brain MRI with and without 
contrast (gadolinium) and spine MRI with and without contrast (gadolinium) must be 
performed at the following time points: 
x 
within 1 week preceding enrollment into the study 
x 
at the following timepoints during protocol therapy: 
o within 1 week prior to each odd-numbered treatment cycle (ie, prior to 
cycles 3, 5, 7, 9, 11, 13) for the first 13 cycles,   
o within 1 week prior to every third treatment cycle (ie, prior to 16, 19, 22, 
25) for cycles 14-26. 
x 
when patient is removed from protocol therapy (upon completion of therapy or at 
progression)  
 
In addition, for patients who have undergone surgical tumor debulking prior to protocol 
therapy, pre-operative and post-operative imaging must be obtained preferably within 48 
hours of surgery.  
 
14.2 
MRI Guidelines for Brain/Spine Tumors 
Juvenile pilocytic astrocytomas and optic pathways gliomas are generally measured on the 
sequence that best demonstrates tumor (usually FLAIR or T2), although this sometimes 
varies. For the purposes of this study, tumors will be measured two-dimensionally using 
the sequence that best demonstrates tumor as determined by the institutional 
neuroradiologist. No additional measurements will be required from the institution.   
 


 
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For recommended brain/spine imaging, required and optional sequences and technical 
details, see the COG CNS Imaging Guidelines posted on the COG member website at: 
https://members.childrensoncologygroup.org/_files/reference/RefMaterial/COGCNSImag
ingGuidelines6_4_10.pdf. 
 
14.3 
Tumor Response Assessment 
For the response assessments, MRI scans obtained at the time-points during protocol 
therapy (see Section 14.1) will be compared to the baseline MRI scan.  Exception: In cases 
of progressive disease, the reference scan should be the MRI with the smallest product 
observed since the start of treatment). 
 
14.4 
Retrospective Central Review 
A retrospective central review of imaging will be performed for all patients enrolled on 
ACNS1022 for determination of best response. Results of the retrospective review will not 
be returned to the site. Submit the following studies with their corresponding reports for 
central review at the completion of treatment or when the patient is removed from protocol 
therapy:  
 
- 
Initial (pre-operative) scan 
- 
Post operative scan (if applicable) 
- 
Recurrence scan (baseline scan) 
- 
Removal from protocol therapy 
- 
Best response (if different from end of treatment scan) (Subsequent evaluations do 
not need to be submitted if no change from earliest best response) 
 
For each study sent to IROC RI (QARC), all imaging sequences obtained (e.g. Precontrast 
T1, FLAIR, T2, diffusion, post contrast T1, etc.) must be submitted. 
 
14.4.1 Address Information 
Submission of Diagnostic Imaging data in digital format is required. Digital files 
must be in DICOM format. These files can be submitted via sFTP. Information for 
obtaining a sFTP account and submission instructions can be found at 
www.QARC.org. Follow the link labeled digital data. Alternatively, if sFTP is not 
feasible, the imaging may be burned to a CD and mailed to IROC RI (QARC) at 
the address below. Multiple studies for the same patient may be submitted on one 
CD; however, please submit only one patient per CD. Sites using Dicommunicator 
may submit imaging via that application. Contact IROC RI (QARC) with questions 
or for additional information. 
Copies of scans of the required studies for central review should be forwarded to: 
 
IROC RI (QARC) 
640 George Washington Highway 
Buildig B, Suite 201 
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
 
Imaging will then be uploaded by IROC RI (QARC) for review by the National 
Cancer Institute (Drs Warren and Patronas). Measurements on T2, FLAIR and T1 
post gadolinium will be taken to determine correlation between sequences and 
patient outcome. 


 
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APPENDIX I:  SITE COUNSELOR IDENTIFICATION FORM 
x 
Please identify at least two (2) counselors There must be two persons at your institution trained. Previous 
trainings for lenalidomide counseling ARE NOT accepted in lieu of the current training. 
x 
 Please fax the request for training form to Celgene at  888-314-2392 
x 
Use one form per counselor. 
x 
Identified counselors must be licensed healthcare professionals (e.g. RN, PA, RPh, PhD, LPN, CNP, or 
MD) and must not be the principal investigator. 
x 
You may list all the protocols and sites that you are requesting training for on the bottom of the form. 
Please add the NCI protocol number(s). 
x 
You will receive e-mail instructions on accessing and completing the training from Celgene. 
x 
Please note: There may be a delay if the handwriting is unclear. Celgene will contact the counselor at the 
phone numbe provided if this is the case. 
x 
Please allow adequate time for Celgene to process your request (3-5 business days) most forms are 
processed withinthe week they are received. If training instructions are no received within this 
timeframs, please e-mail coop_ma@celgene.com to inquire. 
x 
After taking the training, print and fax the Certificate of Completion and your training request form to 
the CTAU at 1-888-691-8039 to ensure the training is applied appropriately to all studies and sites you 
are covering. The CTSU ONLY needs the Certificate of Completion and does no need the additional 
“risk minimization plan” certificates. 
x 
For questions on the training content and scheduling of trainings contact Celgene at 
coop_ma@celgene.com and someone will respond within 24 to 48 hours. 
x 
For questions on study status and CTSU processing of the form contact the CTSU Help Desk at 
ctsucontact@westat.com or 1-888-823-5923. 
 
General Information 
Principal Investigator: ____________________________ Institution Name: _____________________________ 
Celgene 
Corporation 
Celgene Pregnancy Prevention & Counseling Program 
Site Counselor Identification Form 
NCI Protocol #: _______________________________ 
 
Counselor Information  
 
CTEP person ID:  ______________________________  CTEP site ID:  ____________________________________ 
 
First Name: __________________________   Middle Initial:_____   Last Name: ____________________________ 
 
License Type: (circle one)    MD        PhD        PA        CNP        RN        LPN       RPh      Other:_________________ 
 
Email Address:________________________________________________________________________________ 
 
Phone: ___________________________________         Fax:___________________________________________ 
 
Institution Street Address: _______________________________________________________________________ 
 
City: ____________________________________   State/Region: ______________________________________ 
 
Zip/Post Code: _______________________    Country: ______________________________________________ 
 
Which training will you require?   Adult      Pediatric 
 
Were you previously approved as a Counselor?  No  Yes (Previous training)  Adult      Pediatric 


 
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If no, please list all the protocols #(s), corresponding CTEPsiteID(s) and institution names(s) that you plan to provide 
counseling for: 
 
If yes, please list the protocols #(s), corresponding CTEPsiteID(s) and institution names(s) for protocols Celgene has 
already associated you with: 
 
Protocol#: 
CTEPsiteID  
Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX II: LENALIDOMIDE RISKS OF FETAL EXPOSURE, PREGNANCY TESTING 
GUIDELINES AND ACCEPTABLE BIRTH CONTROL METHODS 
 
Risks Associated with Pregnancy 
 
Lenalidomide was teratogenic in both rats and rabbits when administered during the period of 
organogenesis. Thalidomide is a known human teratogen that causes severe life-threatening human birth 
defects.  If Lenalidomide is taken during pregnancy, it may cause birth defects or death to an unborn baby. 
 
 
Definition of female children of childbearing potential (FCCBP)  
 
A FCCBP is a female child who:  
 
• 
Has achieved menarche and/or breast development in Tanner stage 2 or greater  
x 
Onset of fertility typically occurs within 3-12 months after menarche. Menarche varies 
considerably from person to person, and thus no age cut off can be attributed. One of the 
primary tools used to follow a girl’s progress through puberty is the Tanner staging 
system which describes the pattern of development of the secondary sex characteristics. 
Tanner stage 2 corresponds to the beginning of breast development, which is the first 
visible sign of puberty in girls. Breast development is estrogen stimulated, and since 
ovulation cannot occur without estrogen, Tanner stage 2 will be a reliable marker for the 
definition of fertility.   
• 
Has not undergone a hysterectomy or bilateral oophorectomy.   
Note: Amenorrhea following cancer therapy does not rule out childbearing potential    
 
Definition of Female Children NOT of Childbearing Potential (FCNCBP)  
 
A FCNCBP is a female child who:  
• 
has not yet experienced menarche or breast development has not reached Tanner stage 2 or  
• 
has undergone a hysterectomy or bilateral oophorectomy.  
 
Counseling  
 
Female Children of Childbearing Potential (FCCBP) 
 
For a, FCCBP lenalidomide is contraindicated unless all of the following are met (i.e., all female children 
of childbearing potential must be counseled concerning the following risks and requirements prior to the 
start of lenalidomide):   
• 
She understands the potential teratogenic risk to the unborn child  
• 
She understands the need to commence the study treatment as soon as lenalidomide is dispensed 
following a negative pregnancy test  
• 
She understands and accepts the need to undergo pregnancy testing based on the frequency 
outlined in this protocol and in the Informed Consent.  


 
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For FCCBP who do not commit to complete abstinence or plan not to commit to complete abstinence, the 
following are required prior to the start of lenalidomide:  
x 
She understands the need for effective contraception, without interruption, 28 days (4 weeks) 
before starting lenalidomide, throughout the entire duration of lenalidomide, during dose 
interruptions and at least 28 days after the last dose of lenalidomide 
x 
She understands and agrees to inform the Investigator if a change or stop of method of 
contraception is needed 
x 
She must be capable of complying with effective contraceptive measures   
x 
She is informed and understands the potential consequences of pregnancy and the need to notify 
her study doctor immediately if there is a risk of pregnancy  
x 
She acknowledges that she understands the hazards lenalidomide can cause to an unborn fetus and 
the necessary precautions associated with the use of lenalidomide. 
 
The investigator must ensure that:  
• 
A FCCBP complies with the conditions of the PPP, including confirmation that she has an 
adequate level of understanding  
• 
A FCCBP and/or her parent/guardian acknowledge the aforementioned requirements  
Female Children Not of Childbearing Potential 
 
For a FCNCBP, lenalidomide is contraindicated unless all of the following are met (i.e., all FCNCBP must 
be counseled concerning the following risks and requirements prior to the start of lenalidomide):  
  
• 
She and/or her parent/guardian acknowledge an understanding of the hazards lenalidomide can 
cause to an unborn fetus and necessary precautions associated with the use of lenalidomide  
• 
She and/or her parent/guardian will inform site staff as soon as possible regarding new onset of 
menarche  
Male Children 
The effect of lenalidomide on sperm development is not known and has not been studied. The risk to an 
unborn baby in females of child bearing potential whose male partner is receiving lenalidomide is unknown 
at this time. Male subjects taking lenalidomide (and/or his parent/guardian) must meet the following 
conditions (ie, all males must be counseled concerning the following risks and requirements prior to the 
start of lenalidomide): 
x 
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female 
or a female of childbearing potential 
x 
Understand the need for the use of a condom even if he has had a vasectomy, if engaged in 
sexual activity with a pregnant female or a female of childbearing potential. 
x 
Understand the potential teratogenic risk if the subject donates semen or sperm. 
 
 


 
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Contraception  
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable forms of 
contraception simultaneously or to practice complete abstinence (true abstinence is acceptable when this is 
in line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of contraception.) 
from heterosexual contact during the following time periods related to this study:   1) for at least 28  days 
(4 weeks) before starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at 
least 28 days after study treatment discontinuation.   
 
The two methods of reliable contraception must include one highly effective method and one additional 
effective (barrier) method. If the below contraception methods are not appropriate for the FCCBP, she must 
be referred to a qualified provider of contraception methods to determine the medically effective 
contraception method appropriate to the subject. The following are examples of highly effective and 
additional effective methods of contraception:    
x 
Highly effective methods:  
x 
Intrauterine device (IUD)  
 
Hormonal (birth control pills, injections, implants)  
 
Tubal ligation  
 
Partner’s vasectomy  
x 
Additional effective methods:  
 
Male condom  
 
Diaphragm  
 
Cervical Cap  
 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection 
at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered 
particularly in patients with neutropenia.   
 
Male children must practice complete abstinence (true abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, symptothermal or 
post-ovulation methods] and withdrawal are not acceptable methods of contraception.) or agree to use a 
condom during sexual contact with a pregnant female or a female of childbearing potential while taking 
lenalidomide, during dose interruptions and for at least 28 days after the last dose of lenalidomide, even if 
he has undergone a successful vasectomy. 
 
 
 


 
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Pregnancy testing  
 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for 
FCCBP. 
 
Before starting study drug  
 
Female Patients: 
 
FCCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting 
lenalidomide.  The first pregnancy test must be performed within 10-14 days prior to the start of 
lenalidomide and the second pregnancy test must be performed within 24 hours prior to the start of 
lenalidomide.  The patient may not receive study drug until the Investigator has verified that the results of 
these pregnancy tests are negative.  
 
Female children of childbearing potential with regular or no menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of study participation and then every 28 days while taking lenalidomide, 
at study discontinuation, and at Day 28 following the last dose of lenalidomide. 
Female children of childbearing potential with irregular menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of study participation and then every 14 days while taking lenalidomide, 
at study discontinuation, and at Days 14 and 28 following the last dose of lenalidomide. 
 
Male Patients: 
Must practice complete abstinence or  agree to use a condom during sexual contact with a pregnant female 
or a female of childbearing potential while participating in the study, during dose interruptions and for at 
least 28 days following study drug discontinuation, even if he has undergone a successful vasectomy. 
 
During study participation and for at least 28 days following study drug discontinuation  
 
Female Patients: 
 
x 
FCCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 
28 days of study participation and then every 28 days while on study, at study discontinuation, and 
at day 28 following study drug discontinuation.  
 
x 
Female children of childbearing potential with  irregular menstrual cycles, must agree to have 
pregnancy tests weekly for the first 28 days and then every 14 days while on study, at study 
discontinuation, and at days 14 and 28 following study drug discontinuation.  
 
x 
At each visit the Investigator must confirm with the FCCBP that she is continuing to use two 
reliable methods of birth control  
 
x 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted 
at a minimum of every 28 days (once per cycle).   
 
x 
If a FCCBP considers the need to change or to stop a method of contraception, the Investigator 
must be notified immediately. 


 
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x 
If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide must be 
immediately discontinued.  
 
x 
Pregnancy testing and counseling must be performed if a patient misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal.  Study drug treatment must be discontinued 
during this evaluation.  
 
x 
Female children must agree to abstain from breastfeeding during study participation and for at least 
28 days after study drug discontinuation.  
 
Male Patients:  
• 
Must practice complete abstinence (True abstinence is acceptable when this is in line with the preferred 
and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, symptothermal or 
post-ovulation methods] and withdrawal are not acceptable methods of contraception.) or use a condom 
during sexual contact with a pregnant female or a female of childbearing potential while receiving 
lenalidomide, during dose interruptions and for at least 28 days after the last dose of lenalidomide, even 
if he has undergone a successful vasectomy. 
x 
Must not donate semen or sperm while receiving lenalidomide, during dose interruptions and for 
at least 28 days after the last dose of lenalidomide. 
 
x 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted 
at a minimum of every 28 days (once per cycle).   
 
x 
If pregnancy or a positive pregnancy test does occur in the partner of a male study patient during 
study participation, the investigator must be notified immediately.  
 
Additional precautions  
 
Patients should be instructed never to give lenalidomide to another person and to return any unused capsules 
to the Investigator at the end of treatment.  
 
Patients should not donate blood during therapy and for at least 28 days following discontinuation of 
lenalidomide.  
 
Only enough lenalidomide for one cycle of therapy may be dispensed with each cycle of lenalidomide.  
 
 
 


 
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APPENDIX III A: LENALIDOMIDE EDUCATION AND COUNSELING GUIDANCE 
DOCUMENT FOR FEMALE SUBJECTS 
 
To be completed prior to each dispensing of lenalidomide.  
 
Protocol Number: ACNS1022  
 
COG Patient ID#: __________________ DOB: _____/_____/_____ (mm/dd/yyyy)  
 
(Check the appropriate box to indicate risk category) 
 FCCBP (Female children of childbearing potential): female child who: 1) has achieved 
menarche or breast development in Tanner Stage 2 or greater, and 2) has not undergone a 
hysterectomy or bilateral oophorectomy. 
Note: Amenorrhea following cancer therapy does not rule out childbearing potential 
 FCNCBP (Female Children Not of Childbearing Potential): female child who: 1) has not 
experienced menarche or breast development has not reached Tanner Stage 2 or 2) has 
undergone a hysterectomy or bilateral oophorectomy.  
 
Female Child of Childbearing Potential and/or Parent/Guardian: 
 
1. I have verified and counseled the subject and/or parent/guardian regarding the following: 
 Potential risk of fetal exposure to lenalidomide: A teratogenic potential of lenalidomide in 
humans cannot be ruled out. If lenalidomide is taken during pregnancy, it may cause birth 
defects or death to any unborn baby. Females are advised to avoid pregnancy while taking 
lenalidomide. Female children of childbearing potential must agree not to become pregnant 
while taking lenalidomide.  
 That the required pregnancy tests performed are negative. 
 The subject confirmed that she is using TWO reliable methods of birth control at the same 
time, or complete abstinence (True abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) from heterosexual contact (at least 28 days prior to receiving lenalidomide, 
while receiving lenalidomide, during dose interruptions and for at least 28 days after the last 
dose of lenalidomide).  
One highly effective method and one additional method of birth control must be used AT THE 
SAME TIME. The following are examples of highly effective and additional effective methods 
of contraception: 


 
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Examples of highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, ovulation 
inhibitory progesterone-only pills [e.g. desogestrel]) 
o Tubal ligation 
o Partner’s vasectomy 
Examples of additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
 The subject confirmed that even if she has amenorrhea she must comply with advice on 
contraception. 
 Pregnancy tests before, during administration of lenalidomide and at the last dose of 
lenalidomide, even if the subject agrees not to have reproductive heterosexual contact. 
 Frequency of pregnancy tests to be done: 
Two pregnancy tests will be performed prior to receiving lenalidomide, one within 10 to 14 
days, and a second within 24 hours of the start of lenalidomide. 
Every week during the first 28 days of this study and a pregnancy test every 28 days while the 
subject is taking lenalidomide if menstrual cycles are regular.  
Every week during the first 28 days of this study and a pregnancy test every 14 days while the 
subject is taking lenalidomide if menstrual cycles are irregular. 
If the subject missed a period or has unusual menstrual bleeding.   
When the subject is discontinued from the study and at Day 28 after the last dose of 
lenalidomide if menstrual cycles are regular. If menstrual cycles are irregular, pregnancy 
tests will be done at discontinuation from the study and at Days 14 and 28 after the last 
dose of lenalidomide. 
 The subject confirmed that she will stop taking lenalidomide immediately in the event of 
becoming pregnant and to call her study doctor as soon as possible.  


 
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 The subject confirmed that she has not and will not breastfeed a baby while taking lenalidomide 
and for at least 28 days after the last dose of lenalidomide. 
 The subject has not and will never share lenalidomide with anyone else. 
 The subject has not and will not donate blood while taking lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide. 
 The subject has not and will not break, chew, or open lenalidomide capsules at any point. 
 The subject confirmed that she will return unused lenalidomide capsules to the study doctor. 
2. I have provided the Lenalidomide Information Sheet to the subject. 
 
Female Child Not of Childbearing Potential: 
1. I have verified and counseled the female child NOT of childbearing potential and/or her 
parent/guardian regarding the following: 
 The need to be aware of signs of menarche and inform site staff as soon as possible regarding 
onset, if it occurs. 
 Potential risk of fetal exposure to lenalidomide: A teratogenic potential of lenalidomide in 
humans cannot be ruled out. If lenalidomide is taken during pregnancy, it may cause birth 
defects or death to any unborn baby. 
 The subject has not and will never share lenalidomide with anyone else. 
 The subject has not and will not donate blood while taking lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide. 
 The subject has not and will not break, chew, or open lenalidomide capsules at any point. 
 The subject confirmed that she will return unused lenalidomide capsules to the study doctor. 
2. I have provided the Lenalidomide Information Sheet to the subject. 
Do Not Dispense Lenalidomide if: 
x 
The subject is pregnant. 
x 
No pregnancy tests were conducted for a FCCBP. 
x 
The subject states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence from heterosexual contact) at least 28 days prior to 
receiving lenalidomide, while receiving lenalidomide and during dose interruptions. 


 
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x 
The subject stated that she has or does not want to adhere to pregnancy precautions 
outlined within this PPP. 
 
Counselor Name (Print): _________________________  
 
Counselor Signature: _____________________________Date:_____/_____/_____  
 
**Maintain a copy of the Education and Counseling Guidance Document in the patient records. **  


 
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APPENDIX III B: LENALIDOMIDE EDUCATION AND COUNSELING GUIDANCE 
DOCUMENT FOR MALE SUBJECTS 
 
To be completed prior to each dispensing of lenalidomide.  
 
Protocol Number: ACNS1022  
 
COG Patient ID#: __________________ DOB: _____/_____/_____ (mm/dd/yyyy) \ 
 
1. I have verified and counseled the male subject and/or his parent/guardian regarding the following: 
 Potential risks of fetal exposure to lenalidomide: A teratogenic potential of lenalidomide in 
humans cannot be ruled out. If lenalidomide is taken during pregnancy, it may cause birth 
defects or death to any unborn baby. 
 The subject confirmed that he has practiced complete abstinence (True abstinence is acceptable 
when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence 
[eg calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) or used a condom when engaging in sexual contact 
(including those who have had a vasectomy) with a pregnant female or a female of 
childbearing potential, while taking lenalidomide, during dose interruptions and for at least 
28 days after the last dose of lenalidomide.  
 The subject confirmed that he has not impregnated his female partner while in the study. 
 The subject confirmed that he will notify his study doctor if his female partner becomes 
pregnant and the female partner of a male subject taking lenalidomide confirmed that she will 
call her healthcare provider immediately if she becomes pregnant. 
 The subject has not and will never share lenalidomide with anyone else. 
 The subject confirmed that he has not donated and will not donate semen or sperm while taking 
lenalidomide or during dose interruptions and that he will not donate semen or sperm for at 
least 28 days after the last dose of lenalidomide. 
 The subject has not and will not donate blood while taking lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide. 
 The subject has not and will not break, chew, or open lenalidomide capsules at any point. 
 The subject confirmed that he will return unused lenalidomide capsules to the study doctor. 
 
 


 
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2. I have provided the Lenalidomide Information Sheet to the subject. 
Do Not Dispense Lenalidomide if: 
x 
The subject stated that he has or does not want to adhere to pregnancy precautions 
outlined within this PPP. 
 
Counselor Name (Print): _______________________ 
 
 
Counselor 
Signature: 
__________________________Date: 
_____/_____/_____(dd/mmm/yyyy) 
 
**Maintain a copy of the Education and Counseling Guidance Document in the subject’s records. ** 


 
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APPENDIX IV: LENALIDOMIDE PATIENT CARD FOR PEDIATRIC PATIENTS 
 
Protocol Number: ACNS1022  
 
Subject COG ID#: __________________ DOB: _____/_____/_____ (mm/dd/yyyy)  
Investigator to complete each section.  
 
1. Status of Patient (check one)  
 
Female Children NOT of childbearing potential*           
(*no monitoring of pregnancy tests required. Retain card in records)  
 
Male  
 
Female children of child bearing potential              
 
 
 
2. Counseling regarding the potential teratogenicity of lenalidomide 
and the need to avoid pregnancy has been provided before first dose 
dispensed.  
 
 
 
 
3. For Female Children of Childbearing potential – If all fields have 
been used below, print additional Lenalidomide Patient Cards as needed to collect and document results.  
 
 
 
Investigator’s Signature  
Date  
Date of 
Visit  
Date of NEGATIVE 
pregnancy test  
Confirmed no risk 
of pregnancy  
Date lenalidomide 
prescribed  
Investigator’s signature  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX V:  LENALIDOMIDE INFORMATION SHEET  
 
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES 
 
Please read this Lenalidomide Information Sheet before you start taking lenalidomide and each time you 
get a new supply, since there may be new information. This Lenalidomide Information Sheet does not take 
the place of an informed consent to participate in clinical research or talking to your study doctor or 
healthcare provider about your medical condition or your treatment.    
 
What is the most important information I should know about lenalidomide?  
 
Lenalidomide may cause birth defects (deformed babies) or death of an unborn baby. Lenalidomide 
is similar to the medicine thalidomide. It is known that thalidomide causes life-threatening birth defects. 
Lenalidomide has not been tested in pregnant women but may also cause birth defects. Lenalidomide was 
found to cause birth defects when tested in pregnant rabbits. 
 
If you are a female who is able to become pregnant:  
 
x 
Do not take lenalidomide if you are pregnant or plan to become pregnant  
x 
You must either not have any sexual relations with a man or use two reliable, 
separate forms of effective birth control at the same time: 
o for 28 days before starting lenalidomide  
o while taking lenalidomide   
o during dose interruptions of lenalidomide   
o for 28 days after stopping lenalidomide   
x 
You must have pregnancy testing done at the following times:  
o within 10 – 14 days and again 24 hours prior to the first dose of lenalidomide   
o weekly for the first 28 days  
o 
every 28 days after the first month or every 14 days if you have irregular 
menstrual periods  
o if you miss your period or have unusual menstrual bleeding  
o 
28 days after the last dose of lenalidomide (14 and 28 days after the last dose if 
menstrual periods are irregular)  
x 
Stop taking lenalidomide if you become pregnant during lenalidomide treatment  
o 
If you suspect you are pregnant at any time during the study, you must stop 
lenalidomide immediately and immediately inform your study doctor. The 
study doctor will report all cases of pregnancy to the NCI. 
x 
Do not breastfeed while taking lenalidomide and for at least 28 days after thee last 
dose of lenalidomide 
o 
The study doctor will be able to advise you where to get additional advice on 
contraception 
 
 


 
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If you are a female child not able to become pregnant:  
 
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor will confirm that 
you are not able to become pregnant. Any awareness of menstrual periods must be reported to site staff.  
 
If you are a male:  
 
The effect of lenalidomide on sperm development is not known and has not been studies. The rsik to an 
unborn baby in females whose male partneris receiving lenalidomide is unknown at this time. 
 
 
1. Male children, (including those who have had a vasectomy), must either not have any sexual 
relations with a pregnant female or a female who can become pregnant, or must use a condom 
during sexual contact with a pregnant female or a female who that can become pregnant: 
o While you are taking lenalidomide   
o During dose interruptions of lenalidomide   
o For 28 days after you stop taking lenalidomide    
2. Male children should not donate sperm or semen while taking lenalidomide and for 28 days 
after stopping lenalidomide.  
3. If you suspect that your partner is pregnant any time during the study, you must immediately 
inform your study doctor. The study doctor will report all cases of pregnancy to the National 
Cancer Institute. Your partner should call her healthcare provider immediately if she gets 
pregnant. 
All subjects: 
 
x 
Do not share lenalidomide with other people. It must be kept out of the reach of 
children and should never be given to any other person.  
x 
Do not give blood while you take lenalidomide and for 28 days after stopping 
lenalidomide.   
x 
Do not break, chew, or open lenalidomide capsules.  
x 
You will get no more than a 28-day supply of lenalidomide at one time.  
x 
Return unused lenalidomide capsules to your study doctor.  
Additional information is provided in the informed consent form and you can ask your study doctor for 
more information.  


 
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APPENDIX VI: PATIENT DIARY FOR LENALIDOMIDE CAPSULE ADMINISTRATION 
Date: From _____________ To _______________ (4 weeks)  Cycle _______________ 
 
COG Patient ID _________________________ 
ACC#: _________ Institution: ____________________    
Please do not write patient name on this form. 
 
My daily dose of lenalidomide is:_______ mg, (____ 2.5 mg capsule, _____ 5 mg capsule, ______ 25 mg capsule)  
once a day for 21 days.  
1 
Take/give lenalidomide dose by mouth with a full glass of water. The lenalidomide capsules should not be 
opened, broken or chewed. 
2 
Take/give the medication at a convenient time approximately the same time each day for 21 days (THREE 
weeks). You should take/give the medication without food. If nausea occurs after taking the dose, try 
taking/giving it with food as administration with food may decrease nausea. 
3 
Write down date, number of capsule(s) you gave/took. Wash your hands if you touch the pills. 
4 
If you forget to take/give the dose on time and you remember that a dose is missed within 8 hours, take the 
missed dose. If more than 8 hours have passed then skip that dose. Notify the clinic that a dose was taken 
late or skipped at the next visit. 
5 
If you vomit within 10 minutes of taking the dose and you can see the capsules, take another dose and notify 
the clinic. You may need to obtain additional supply of drug to finish the cycle. 
6 
Write down any side effects (like diarrhea, constipation, nausea) in the comments column. 
7 
Bring your capsule bottle and this form to your doctor when you return to your next appointment.  
Date 
Day 
# Capsules 
(list strength 
and quantity) 
Comments 
(example: 
diarrhea, constipation, 
nausea) 
Date 
Day 
# Capsules 
(list 
strength 
and 
quantity) 
Comments 
(example: diarrhea, 
constipation, 
nausea) 
 
1 
 
 
 
15 
 
 
 
2 
 
 
 
16 
 
 
 
3 
 
 
 
17 
 
 
 
4 
 
 
 
18 
 
 
 
5 
 
 
 
19 
 
 
 
6 
 
 
 
20 
 
 
 
7 
 
 
 
21 
 
 
 
8 
 
 
 
22 
Rest period 
of 7 days 
 
 
9 
 
 
 
23 
 
 
10 
 
 
 
24 
 
 
11 
 
 
 
25 
 
 
12 
 
 
 
26 
 
 
13 
 
 
 
27 
 
 
14 
 
 
 
28 
 
Patient’s/Caregiver Signature: __________________________  Date: _________________________ 
Physician’s Office will complete this section: 
1.   Date patient started protocol treatment  _________   Date patient was removed from study _______________ 
2.   Patient’s planned daily dose ______________________     
 
Physician/Nurse/Data Manager’s Signature ______________________________________________ 


 
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Page 80 
 
 
APPENDIX VII: ACNS1022 PHARMACOKINETIC STUDY FORM: STEADY STATE SAMPLES 
 
COG Pt ID # _______________ 
ACC # _______________ 
 
Please do not write patient names on this form or on samples. 
 
Cycle ____, Day______ Date:  |__/__|__/__|__/__| 
 
 
Body Surface Area: |__|°|__|__| m
2 
 
Total Dose: |__| |__| |__|°|__| |__| mg 
 
Blood samples (2 mL) will be drawn peripherally in green top (sodium heparin) tubes. Please see protocol 
Section 13.1 for detailed Sample Collection, Handling, and Processing instructions. Record the exact time that 
the sample is drawn along with the exact time that the drug was administered after sample collection. 
 
 
 
 
Date Sample 
Collected 
Time Sample 
Collected 
Administration of 
Lenalidomide 
Blood 
Sample 
No. 
Collection Time (prior to drug 
administration) 
 
 
Date 
Time 
1 
Cycle 1,  
Between Days 5-21 
Date: _______ 
Time: _____ 
Date: ___ 
Time: ____ 
2 
Cycle following a first dose 
reduction, 
Any day between Days 5-21 
Date: _______ 
 
Time: _____ 
Date: ___ 
Time: ____ 
3 
Cycle following a second dose 
reduction, 
Any day between Days 5-21 
Date: _______ 
 
Time: _____ 
Date: ___ 
Time: ____ 
 
Each tube must be labeled with “ACNS1022”, the patient’s COG number, the date and time the sample was 
drawn, and the designated time point that the sample represents (eg, “Cycle 1, Day X”). Data should be recorded 
on this Pharmacokinetic Study Form, which must accompany the sample(s). 
 
Please see Section 13.1 for detailed sample shipping instructions. Prior to shipping, please contact Dr. Brigitte 
Widemann (301-496-7387) for notification of sample shipment. DO NOT SHIP SAMPLES ON A FRIDAY 
OR WEEKEND. Refer to the following link for information regarding Federal Express Account information to 
use for shipping pk samples: https://members.childrensoncologygroup.org/prot/biology.asp.  Ship samples 
to: 
Widemann Laboratory 
Pediatric Oncology Branch, NCI, CCR 
10 Center Dr. 10-CRC, Rm 1-5750 MSC 1101 
Bethesda, MD 20892-1928   
Phone: 301-496-7387 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date 
this form below: 
Signature: __________________________________________ 
 
Date: ____________________ 
 
(site personnel who collected samples) 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ACNS1022 
Version Date: 6/1/2018 
 
Page 81 
 
 
APPENDIX VIII:  YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS1022 
(for children from 7 through 12 years of age) 
 
A Study of An Experimental Drug in Children and Teens with Brain Tumors 
That are Hard to Treat or Have Come Back after Treatment 
 
1. We have been talking with you about your brain tumor. Your brain tumor has either come back or 
not gone away with the treatments you already received. 
 
2. We are asking you to take part in a research study because other treatments did not get rid of your 
tumor. 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 find out if an experimental anti-cancer medicine can make your 
tumor get smaller or go away.  
 
3. Children who are part of this study will be treated with the anti-cancer medicine called 
lenalidomide. This medicine has been used to treat children with different kinds of cancers, 
including brain cancer. In this study, we want to treat more children with brain cancers so we can 
get more information about how well lenalidomide works.  This study will look at two doses of the 
anti-cancer medicine. Half of the children in this study will get a lower dose of the anti-cancer 
medicine and half will get a higher dose. Which dose you get will get is decided on by chance. This 
is like flipping a coin and saying, “Heads means I get the lower dose treatment, but tails means I 
get the higher-dose treatment.” A computer decides which treatment you will get, not you or your 
doctor. 
 
4. 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 the new anti-
cancer medicine will make your tumor get smaller or go away for as long as possible.  But, we do 
not know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks.”  One risk to you from this study is that the study treatment may not work as well 
as other treatments to make your tumor get smaller or go away for as long as possible. Other things 
may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not.  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.  Make sure to ask your doctors any questions that you have. 
 
7. We are asking your “okay” to collect extra blood.  We want to see if there are ways to tell how the 
tumor will react to treatment. We would like to collect about ½ teaspoon of blood at up to 3 times 
during your treatment. We will try to collect the extra blood at the same time other standard blood 
tests are being done. If we can’t do this, you might have up to two extra needle sticks.   


 
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Page 82 
 
 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS1022 
(for teens from 13 through 17 years of age) 
 
A Study of An Experimental Drug in Children and Teens with Brain Tumors 
That are Difficult to Treat or Have Come Back after Treatment 
 
1. We have been talking with you about your low grade glioma. Low grade gliomas are types of cancer 
that grow in the brain. Your tumor has either come back or not gone away with previous treatments.  
 
2. We are asking you to take part in a research study because other treatments did not get rid of your 
low grade glioma. A research study is when doctors work together to try out new ways to help 
people who are sick.  In this study, doctors want to try an experimental anti-cancer drug to see if 
this drug will work well to make your tumor get smaller or go away. 
 
3. All children and teens who are part of this study will be treated with the anti-cancer drug called 
lenalidomide. This drug has been used to treat children and teens with different types of cancer, 
including some children and teens with brain cancer. In this study, doctors would like to treat a 
larger group of children and teens with brain cancers so they can get more information about how 
well lenalidomide works.  This study will look at two doses of the anti-cancer drug. Half of the 
children in this study will get a lower dose of the anti-cancer drug and half will get a higher dose. 
Which dose you get will get is decided on by chance. This is like flipping a coin and saying, “Heads 
means I get the lower dose treatment, but tails means I get the higher-dose treatment.” A computer 
decides which treatment you will get, not you or your doctor. 
 
4. 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 the 
lenalidomide will make your tumor get smaller or go away for as long as possible, but we don’t 
know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks.”  One risk to you from this study is that the treatment you get may not work as 
well as other treatments to get rid of the tumor for as long as possible.  Another risk is that you may 
have more side effects from the drug if you get the higher dose. If you get the lower dose, there is 
a risk is that you may get a treatment that does not work as well as the higher dose. Other things 
may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not.  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. Make sure to ask your doctors any questions that you have.  
 
7. We are asking your permission to collect additional blood.  We want to see if there are ways to tell 
how the cancer will respond to treatment. We would like to collect about ½ teaspoon of blood at 
up to 3 times during your treatment. We will try to collect the extra blood at the same time other 
standard blood tests are being performed. If we can’t do this, you might have up to two extra needle 
sticks.  
 
 
 


 
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Version Date: 6/1/2018 
 
Page 83 
 
 
 APPENDIX IX:  REGIMEN A LENALIDOMIDE DOSING TABLES  
 
 
  
 
 
 
 
 
 
15 mg/m2, 
Dose Level -1 
BSA (m2) 
Daily Dose 
(mg) 
0.44 – 0.56 
7.5 
0.57 – 0.75 
10 
0.76 – 0.91 
12.5 
0.92 – 1.08 
15 
1.09 – 1.25 
17.5 
1.26 – 1.42 
20 
1.43 – 1.58 
22.5 
1.59 – 1.76 
25 
1.77 – 1.91 
27.5 
1.92 – 2.08 
30 
2.09 – 2.20 
32.5 
 
Round to 
nearest 2.5 
mg 
10 mg/m2, 
Dose Level -2 
BSA (m2) 
Daily Dose 
(mg) 
0.44 – 0.62 
5 
0.63 – 0.82 
7.5 
0.83 – 1.12 
10 
1.13 – 1.37 
12.5 
1.38 – 1.62 
15 
1.63 – 1.87 
17.5 
1.88 – 2.12 
20 
2.13 – 2.20 
22.5 
 
Round to 
nearest 2.5 mg 
20 mg/m2, 
Dose Level 1 
BSA (m2) 
Daily Dose 
(mg) 
0.44 – 0.56 
10 
0.57 – 0.69 
12.5 
0.70 – 0.81 
15 
0.82 – 0.93 
17.5 
0.94 – 1.06 
20 
1.07 – 1.18 
22.5 
1.19 – 1.31 
25 
1.32 – 1.43 
27.5 
1.44 – 1.56 
30 
1.57 – 1.69 
32.5 
1.70 – 1.82 
35 
1.83 – 1.94 
37.5 
1.95 – 2.06 
40 
2.07 – 2.19 
42.5 
 
Round to 
nearest 2.5 
mg 


 
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Page 84 
 
 
APPENDIX X:  CTEP AND CTSU REGISTRATION PROCEDURES 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all investigators participating in any NCI-sponsored clinical trial to register and to renew 
their registration annually. 
 
Registration requires the submission of: 
 
x 
a completed Statement of Investigator Form (FDA Form 1572) with an original signature 
x 
a current Curriculum Vitae (CV) 
x 
a completed and signed Supplemental Investigator Data Form (IDF) 
x 
a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>. For questions, please 
contact 
the 
CTEP 
Investigator 
Registration 
Help 
Desk 
by 
email 
at 
<pmbregpend@ctep.nci.nih.gov>. 
 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all physicians 
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in 
the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP 
Investigator Registration Procedures above for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials 
Support Unit) websites and applications, including the CTSU members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>. For questions, please contact 
the CTEP Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements for ACNS1022 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI 
CIRB)  


 
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Page 85 
 
 
 
Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval to the CTSU Regulatory Office, 
where they will be entered and tracked in the CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 
215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS site registration status page 
of the members’ section of the CTSU website. (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
 
 
 


 
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Page 86 
 
 
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Version Date: 6/1/2018 
 
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