Clinical trial NCT01979536
Conditions: Anaplastic Large Cell Lymphoma, ALK-Positive Ann Arbor Stage II Noncutaneous Childhood Anaplastic Large Cell Lymphoma Ann Arbor Stage III Noncutaneous Childhood Anaplastic Large Cell Lymphoma Ann Arbor Stage IV Noncutaneous Childhood Anaplastic Large Cell Lymphoma
Sponsor: National Cancer Institute (NCI)
Start date: 2013-11-13; Completion date: 2024-03-31
Enrollment: 137 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This partially randomized phase II trial studies how well brentuximab vedotin or crizotinib and combination chemotherapy works in treating patients with newly diagnosed stage II-IV anaplastic large cell lymphoma. Brentuximab vedotin is a monoclonal antibody, called brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30 positive cancer cells in targeted way and delivers vedotin to kill them. Crizotinib and methotrexate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether brentuximab vedotin and combination chemotherapy is more effective than crizotinib and combination chemotherapy in treating anaplastic large cell lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the tolerability of brentuximab vedotin given in combination with standard chemotherapy (anaplastic large cell lymphoma \[ALCL\]99) and to determine the tolerability of crizotinib given in combination with chemotherapy (ALCL99).

II. To estimate the event free survival (EFS) of Arm brentuximab vedotin (BV) and Arm crizotinib (CZ) and contrast these to historical control data.

SECONDARY OBJECTIVES:

I. To determine the prognostic significance of minimal disseminated disease (MDD) at diagnosis and minimal residual disease (MRD) as measured by real-time (RT)-polymerase chain reaction (PCR) in peripheral blood.

OUTLINE: Patients with body surface area (BSA) \< 0.9 m\^2 were non-randomly assigned to Arm BV while it was open and were not eligible for the trial while Arm BV was closed. Patients with BSA \>= 0.9 m\^2 were randomly assigned 1:1 to Arm BV or Arm CZ while both were open and were non-randomly assigned to the open arm while only one of the two arms was open.

ARM BV:

COURSE A (CYCLES 1, 3, AND 5): Patients receive brentuximab vedotin (1.8 mg/dg/dose - Max dose 180 mg) intravenously (IV) over 30 minutes on day 1, dexamethasone orally (PO) twice daily (BID) or IV on days 1-5, ifosfamide IV over 60 minutes on days 1-5, methotrexate IV over 3 hours on day 1, cytarabine IV over 1-30 minutes every 12 hours for 4 doses on days 4 and 5, and etoposide IV over 2 hours on days 4 and 5.

COURSE B (CYCLES 2, 4, AND 6): Patients receive brentuximab vedotin (1.8 mg/dg/dose - Max dose 180 mg), dexamethasone, and methotrexate as in Arm BV, Course A. Patients also receive cyclophosphamide IV over 15-30 minutes on days 1-5 and doxorubicin hydrochloride IV over 1-15 minutes on days 4 and 5.

ARM CZ:

COURSE A (CYCLES 1, 3, AND 5): Patients receive crizotinib (165 mg/m\^2) PO BID on days 1-21 and dexamethasone, ifosfamide, methotrexate, cytarabine, and etoposide as in Arm BV, Course A.

COURSE B (CYCLES 2, 4, AND 6): Patients receive crizotinib (165 mg/m\^2) PO BID as in Arm CZ, Course A and dexamethasone, cyclophosphamide, methotrexate, and doxorubicin hydrochloride as in Arm BV, Course B.

In all arms, treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months.

Arms: arm 1: COURSE A (CYCLES 1, 3, AND 5): Patients receive brentuximab vedotin IV over 30 minutes on day 1, dexamethasone PO BID or IV on days 1-5, ifosfamide IV over 60 minutes on days 1-5, methotrexate IV over 3 hours on day 1, cytarabine IV over 1-30 minutes every 12 hours for 4 doses on days 4 and 5, and etoposide IV over 2 hours on days 4 and 5.

COURSE B (CYCLES 2, 4, AND 6): Patients receive brentuximab vedotin, dexamethasone, and methotrexate as in Arm BV, Course A. Patients also receive cyclophosphamide IV over 15-30 minutes on days 1-5 and doxorubicin hydrochloride IV over 1-15 minutes on days 4 and 5. arm 2: COURSE A (CYCLES 1, 3, AND 5): Patients receive crizotinib PO BID on days 1-21 and dexamethasone, ifosfamide, methotrexate, cytarabine, and etoposide as in Arm BV, Course A.

COURSE B (CYCLES 2, 4, AND 6): Patients receive crizotinib PO BID as in Arm CZ, Course A and dexamethasone, cyclophosphamide, methotrexate, and doxorubicin hydrochloride as in Arm BV, Course B.
Interventions: intervention 1: Brentuximab Vedotin intervention 2: Crizotinib intervention 3: Cyclophosphamide intervention 4: Cytarabine intervention 5: Dexamethasone intervention 6: Doxorubicin Hydrochloride intervention 7: Etoposide intervention 8: Ifosfamide intervention 9: Methotrexate
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO intervention 3: Given IV intervention 4: Given IT and IV intervention 5: Given PO or IV intervention 6: Given IV intervention 7: Given IV intervention 8: Given IV intervention 9: Given IT and IV

Protocol documents:
Prot_SAP_000.pdf: 
  
 
i 
 
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 
 
 
 
 
February 1, 2019 
 
 
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, 
 
Enclosed please find Amendment #9 to protocol ANHL12P1, A Randomized Phase 2 Trial 
of Brentuximab Vedotin (SGN35, NSC# 749710), or Crizotinib (NSC#749005, 
commercially labeled) in Combination with Chemotherapy for Newly Diagnosed Patients 
with Anaplastic Large Cell Lymphoma (ALCL) for CTEP review. 
 
This amendment is being submitted in response to a Request for Rapid Amendment 
(RRA) from Dr. John J. Wright (wrighttj@ctep.nci.nih.gov), dated January 22, 2019. In this 
amendment, the revised CAEPR for Crizotinib (Version 2.3, October 30, 2018) has been 
inserted in the protocol, and the associated risk information in the informed consent 
document has been revised accordingly.  
 
In addition, changes have been made in response to a RRA for SGN-35 (brentuximab 
vedotin) from Dr. Elad Sharon (sharone@mail.nih.gov), dated June 13, 2018. A notation 
has been made in the protocol to indicate that the SGN-35 arm is closed to accrual and 
treatment and that the CAEPR will not be updated further. The associated risk information 
in the informed consent document has been revised accordingly.  
 
Revisions to the protocol and consent document are detailed in the pages below. 
 
Please let me know if we can offer further information. 
 
Sincerely, 
 
Jeannette Cassar, Protocol Coordinator (for) 
Eric Lowe, MD, ANHL12P1 Study Chair 
Peter Adamson, MD, COG Group Chair 
 


 
 
 
 
 
ii 
 
 
SUMMARY OF CHANGES: PROTOCOL 
In accordance with the above discussion, the following specific revisions have been made to the protocol.  
 
# 
Section 
Page(s) 
Change 
1.  
General 
- 
Updated protocol version date in the footer.  
2.  
Title Page 
1 
Update version date and amendment number 
3.  
6.1.10 
56 
Added the following notation: “The arm using SGN-35 (brentuximab 
vedotin, NSC 749710) is closed to accrual and treatment.  The 
CAEPR is no longer being updated.” 
4.  
6.2 
60 
• 
Updated the monograph date. 
• 
Removed “commercially labeled” and added the IND number.  
5.  
6.2.8 
61-64 
Updated the toxicity section with the new CAEPR and toxicity 
information.  
 
 
 
SUMMARY OF CHANGES: INFORMED CONSENT 
In accordance with the above discussion, the following specific revisions have been made to the consent.  
 
# 
Section 
Page(s) 
Change 
1.  
General 
All 
Updated version date of consent to match the current version of 
the protocol. 
2.  Possible Side Effects 
of SGN-35 
9 
Updated the possible side effects of SGN-35 to match the NCI 
provided template.  
3.  Possible Side Effects 
of Crizotinib 
10-11 
Updated the possible side effects of Crizotinib to match the NCI 
provided template. 
 


 
 
 
ANHL12P1 
 
Version Date: 02/01/2019 
1 
 
 
 
Activated: 
11/08/13 
Version Date: 
02/01/2019 
Closed: 
      
Amendment: 
9 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
ANHL12P1 
 
A Randomized Phase 2 Trial of Brentuximab Vedotin (SGN35, NSC# 749710), or Crizotinib 
(NSC#749005, commercially labeled) in Combination with Chemotherapy for Newly Diagnosed 
Patients with Anaplastic Large Cell Lymphoma (ALCL) 
 
 
 
A COG Groupwide Phase II Study (Limited to US sites) 
 
 
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. 
 
 
NCI Supplied Agents : 
Brentuximab Vedotin (SGN35, NSC# 749710) 
Crizotinib (NSC#749005) 
 
STUDY CHAIR 
Eric J. Lowe, M.D. 
Children’s Cancer and Blood Disorder Center 
Children’s Hospital of the King’s Daughters 
601 Children’s Lane 
Norfolk, VA 23507 
Phone: (757) 668-9772 
Fax: 
(757) 668-6171 
E-mail: eric.lowe@chkd.org 


 
 
 
 
ANHL12P1 
Version Date: 02/01/2019 
2 
 
CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Please see the 
Data Submission Schedule in the 
CRF packet for further 
instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Access to the CTSU 
members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and password. 
Permission to view and download this protocol and its supporting documents is restricted and is based on person 
and site roster assignment housed in the CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead Protocol 
Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence 
will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 


 
 
 
 
ANHL12P1 
Version Date: 02/01/2019 
3 
 
TABLE OF CONTENTS 
 
SECTION  
PAGE 
TABLE OF CONTENTS 
3 
STUDY COMMITTEE 
8 
ABSTRACT 
10 
EXPERIMENTAL DESIGN SCHEMA 
11 
1.0 
GOALS AND OBEJCTIVES 
12 
1.1 
Primary Aims 
12 
1.1.1 
Tolerability 
12 
1.1.2 
Event Free Survival 
12 
1.2 
Secondary Aim 
12 
1.2.1 
MDD/MRD 
12 
2.0 
BACKGROUND 
12 
2.1 
Introduction/Rationale for Development 
12 
2.2 
Brentuximab vedotin Background 
13 
2.3 
Crizotinib Background 
15 
2.4 
Study Rationale 
16 
2.4.1 
Rationale for ALCL99 
16 
2.4.2 
Rationale for eligibility 
16 
2.4.3 
Rationale for brentuximab vedotin and crizotinib 
16 
2.5 
Biology 
17 
2.5.1 
Minimal Disseminated Disease (MDD) / Minimal Residual Disease (MRD) 
17 
2.6 
Thromboembolic Background 
18 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
18 
3.1 
Study Enrollment 
18 
3.1.1 
Patient Registration 
18 
3.1.2 
IRB Approval 
19 
3.1.3 
Study Enrollment 
20 
3.1.4 
Timing 
20 
3.1.5 
Randomization 
21 
3.2 
Patient Eligibility Criteria 
21 
3.2.1 
Age 
21 
3.2.2 
Diagnosis 
21 
3.2.3 
Life Expectancy 
22 
3.2.4 
Organ Function Requirements 
22 
3.2.5 
Exclusion Criteria 
22 
3.2.6 
Regulatory Requirements 
23 
4.0 
TREATMENT PROGRAM 
24 
4.1 
Overview of Treatment Plan 
24 
4.1.1 
Supportive Care Guidelines 
24 
4.1.2 
Concomitant Therapy Restrictions 
25 
4.2 
Prophase (5 days) – Arms BV and CZ 
26 
4.2.1 
Prophase (5 days) Arm BV and CZ 
27 
4.3 
Course A (21 days) – Arm BV (Cycles 1, 3 and 5) 
28 
4.3.1 
Course A (21 days) - Arm BV (Cycles 1, 3 & 5) 
32 
4.4 
Course B (21 days) – Arm BV (Cycles 2, 4 and 6) 
33 


 
 
 
 
ANHL12P1 
Version Date: 02/01/2019 
4 
 
4.4.1 
Course B (21 days) – Arm BV (Cycles 2, 4 and 6) 
36 
4.5 
Course A (21 days) – Arm CZ (Cycles 1, 3 and 5) 
37 
4.5.1 
Course A (21 days) – Arm CZ (Cycles 1, 3 and 5) 
40 
4.6 
Course B (21 days) – Arm CZ (Cycles 2, 4 and 6) 
41 
4.6.1 
Course B (21 days) – Arm CZ (Cycles 2, 4 & 6) 
44 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
45 
5.1 
Brentuximab vedotin (SGN-35) 
45 
5.1.1 
Suggested Dose Modifications/Delays guidelines 
45 
5.2 
Crizotinib 
48 
5.2.1 
Hematological Toxicity 
48 
5.2.2 
Therapy Delay 
48 
5.2.3 
Hepatic Toxicity 
48 
5.2.4 
Renal Cyst 
48 
5.3 
Cyclophosphamide 
51 
5.3.1 
Hematuria 
51 
5.3.2 
Renal Dysfunction 
51 
5.4 
Dexamethasone 
51 
5.4.1 
Hypertension 
51 
5.4.2 
Hyperglycemia 
51 
5.4.3 
Pancreatitis 
51 
5.4.4 
Varicella 
51 
5.4.5 
Inability to use oral doses 
51 
5.5 
Doxorubicin 
52 
5.5.1 
Cardiac Toxicity 
52 
5.5.2 
Hyperbilirubinemia 
52 
5.5.3 
Mucositis 
52 
5.6 
Etoposide 
52 
5.6.1 
Allergic Reaction 
52 
5.6.2 
Hypotension 
52 
5.6.3 
Renal Insufficiency 
52 
5.6.4 
Hyperbilirubinemia 
52 
5.7 
Ifosfamide 
53 
5.7.1 
Hematuria 
53 
5.7.2 
Neurotoxicity 
53 
5.7.3 
Nephrotoxicity 
53 
5.8 
Methotrexate 
53 
5.8.1  
Nephrotoxicity 
53 
5.8.2  
Hepatic Toxicity 
53 
6.0 
DRUG INFORMATION 
54 
6.1 
Brentuximab vedotin                                                                                        11/09/15 54 
6.1.1 
Structure and molecular weight 
54 
6.1.2 
Supplied by 
54 
6.1.3 
Formulation 
54 
6.1.4 
Storage 
54 
6.1.5 
Solution Preparation 
54 
6.1.6 
Stability 
55 
6.1.7 
Administration 
55 
6.1.8 
Potential drug interactions: 
55 
6.1.9 
Patient Care Implications 
56 


 
 
 
 
ANHL12P1 
Version Date: 02/01/2019 
5 
 
6.1.10 Toxicity 
56 
6.1.11 Clinical Drug Request 
59 
6.1.12 Agent Inventory Records 
59 
6.2 
Crizotinib 01/23/2019 
60 
6.2.1 
Structure and molecular weight 
60 
6.2.2 
Supplied by 
60 
6.2.3 
Formulation 
60 
6.2.4 
Storage 
60 
6.2.5 
Handling 
60 
6.2.6 
Stability 
60 
6.2.7 
Administration 
61 
6.2.8 
Toxicity 
61 
6.2.9 
Agent Ordering and Agent Accountability 
64 
6.2.10 Clinical Drug Request 
64 
6.2.11 Agent Inventory Records 
65 
6.3 
CYCLOPHOSPHAMIDE - INJECTION 
65 
6.4 
CYTARABINE 
66 
6.5 
DEXAMETHASONE 
68 
6.6 
DOXORUBICIN 
70 
6.7 
ETOPOSIDE - INJECTION 
72 
6.8 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ 
74 
6.9 
IFOSFAMIDE 
76 
6.10 
INTRATHECAL TRIPLES 
78 
6.11 
LEUCOVORIN CALCIUM 
79 
6.12 
MESNA - INJECTION 
81 
6.13 
METHOTREXATE - IV only 
82 
6.14 
PEGFILGRASTIM 
84 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
86 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
86 
7.2 
Follow-up 
87 
7.2.1 
Follow-up Table 
87 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
88 
8.1 
Criteria for Removal from Protocol Therapy 
88 
8.2 
Off Study Criteria 
88 
9.0 
STATISTICAL CONSIDERATIONS 
88 
9.1 
Sample Size and Study Duration 
88 
9.2 
Study Design 
88 
9.2.1 
Primary study endpoint: 
89 
9.2.2 
Secondary study endpoints: 
91 
9.3 
Methods of Analysis 
92 
9.4 
Evaluability for Toxicity 
92 
9.5 
Gender and Minority Accrual Estimates 
92 
10.0 
EVALUATION CRITERIA 
93 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
93 
10.2 
Response Criteria Overview 
93 
10.3 
Response Criteria for Patients with ALCL 
94 
10.3.1 Complete Response (CR) 
94 


 
 
 
 
ANHL12P1 
Version Date: 02/01/2019 
6 
 
10.3.2 Complete Response Unconfirmed (CRu) 
94 
10.3.3 Partial Response (PR) 
94 
10.3.4 No Response (Stable Disease) 
94 
10.3.5 Progressive disease (PD) 
95 
10.3.6 Duration of Response 
95 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
96 
11.1 
Purpose 
96 
11.2 
Determination of reporting requirements 
96 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
96 
11.4 
Special Situations for Expedited Reporting 
97 
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
97 
11.4.2 Persistent or Significant Disabilities/Incapacities 
97 
11.4.3 Death 
97 
11.4.4 Secondary Malignancy 
98 
11.4.5 Second Malignancy 
98 
11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
98 
11.5 
Reporting Requirements for Specialized AEs 
99 
11.5.1 Baseline AEs 
99 
11.5.2 Persistent AEs 
99 
11.5.3 Recurrent AEs 
100 
11.6 
Exceptions to Expedited Reporting 
100 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
100 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
100 
11.7 
Reporting Requirements - Investigator Responsibility 
100 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
100 
11.9 
Reporting Table for Phase 1 and Early Phase 2 Studies 
102 
11.10 
Protocol Specific Additional Instructions and Reporting Exceptions 
103 
11.11 
Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway
 
103 
11.12 
Routine Adverse Event Reporting 
104 
12.0 
STUDY REPORTING AND MONITORING 
104 
12.1 
CDUS 
104 
12.2 
Data Safety and Monitoring Committee 
104 
12.3 
CRADA/CTA 
105 
13.0 
PATHOLOGY GUIDELINES AND SPECIAL STUDIES 
107 
13.1 
Pathology Guidelines 
107 
13.1.1 Pathology Goals 
107 
13.1.2 Requirements for Handling Tissue or Cytology Specimens at Primary Institutions
 
107 
13.1.3 Immunophenotyping Recommendations for Primary Institutions 
107 
13.1.4 Morphology 
107 
13.1.5 Bone Marrow 
108 
13.1.6 Study Pathologists 
108 
13.2 
Specimens to Submit For Central Pathology Review 
109 
13.2.1 List of Specimen Types 
109 
13.2.2 Pathology Reports 
109 
13.2.3 Pathology Data Collection Forms (Institutional Pathology Form) 
109 
13.2.4 Submission of Pathology Review Materials 
110 
13.3 
Special Tissue Banking 
110 


 
 
 
 
ANHL12P1 
Version Date: 02/01/2019 
7 
 
13.3.1 Tissue Banking 
110 
13.4  
Peripheral Blood Studies for MDD/MRD (Required) 
110 
13.4.1 Shipment of Peripheral Blood 
111 
14.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
112 
15.0 
SURGICAL GUIDELINES 
112 
15.1 
Role of the Surgeon 
112 
APPENDIX I: STAGING 
113 
APPENDIX II: PERFORMANCE STATUS CRITERIA 
114 
APPENDIX III: CTEP REGISTRATION PROCEDURES 
115 
APPENDIX IV: COMMON SUBSTRATES, INHIBITORS AND INDUCERS OF CYP3A4 
118 
APPENDIX V: CRIZOTINIB DOSING TABLES 
120 
APPENDIX VI: POSSIBLE DRUG INTERACTIONS 
121 
APPENDIX VII: YOUTH INFORMATION SHEETS 
128 
REFERENCES 
130 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
8 
 
 
STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Eric Jeffrey Lowe, MD 
Debbie A. Woods, MSN, CPNP  
Children’s Hospital-King's Daughters 
Nursing 
Pediatric Hematology/Oncology 
University of California Davis Comprehensive Cancer Center 
601 Children's Lane 
Pediatric Hematology/Oncology  
Norfolk, Virginia  23507 
2279 45th Street 
Phone: (757) 668-7243  
Sacramento, CA 95817 
Fax: 
(757) 668-7811 
Phone: (916) 734-4899 
E-mail:   eric.lowe@chkd.org  
Fax: 
(916) 734-0980 
 
E-mail: dwoods@ucdavis.edu   
STUDY CO-VICE CHAIR 
 
John T. Sandlund, MD 
JoEllen Louise Weilnau, PharmD  
Oncology  
Pharmacy  
Saint Jude Children's Research Hospital  
Children's Hospital Medical Center of Akron  
262 Danny Thomas Place, MS 260  
One Perkins Square 
Memphis, TN 38105-3678 
Akron, OH 44308 
Phone: (901) 595-2427  
Phone: (330) 543-4601  
Fax: 
(901) 521-9005  
Fax:  
(330) 543-4436 
E-mail: john.sandlund@stjude.org  
E-mail: jweilnau@akronchildrens.org 
 
 
STUDY CO-VICE CHAIR 
Megan So-Young Lim, MD, PhD  
Anne Fitzpatrick Reilly, MD 
Pathology 
Hematology/Oncology 
Children's Hospital of Philadelphia 
Children's Hospital of Philadelphia  
Department of Pathology and Laboratory Medicine 
Division of Oncology 
422 Curie Blvd. 
34th & Civic Center Blvd 
Room 609 Stellar-Chance 
Philadelphia PA 19104 
Philadelphia, PA 19104 
Phone: (215) 590-0936  
Phone: (215) 898-2925 
Fax: 
(215) 590-4183  
Fax: 
(215) 662-7529 
E-mail: reillya@email.chop.edu   
E-mail: megan.lim@uphs.upenn.edu   
 
 
STUDY COMMITTEE MEMBERS  
Rebecca Alice Emmons Gardner, MD 
Robert E. Hutchison, MD 
Hematology/Oncology  
SUNY Upstate Medical University 
Seattle Children's Hospital  
Pathology 
Hematology/Oncology  
750 East Adams Street 
M/S MB.8.501, PO Box 5371 
Syracuse, NY 13210 
Seattle, WA 98145 
Phone: (315) 464-6771 
Phone: (206) 667-1317 
Fax: 
(315) 464-7322 
Fax: 
(206) 987-3946 
E-mail: hutchisb@upstate.edu  
E-mail: rebecca.emmons@seattlechildrens.org 
 
 
Thomas Gene Gross, MD, PhD 
STUDY STATISTICIAN 
National Cancer Institute 
Donald A. Barkauskas, PhD 
NCI-Center of Global Health 
Children's Oncology Group 
9609 Medical Center Drive, 3W534 
Group Operations Center 
Rockville, MD 20850 
222 E. Huntington Drive, Suite 100 
Phone: (240) 276-6984 
Monrovia, CA 91016 
Fax: 
(240) 276-5820  
Phone: (626) 241-1540 
E-mail: Thomas.Gross@nih.gov  
Fax: 
(626) 445-4334 
 
E-mail: dbarkauskas@childrensoncologygroup.org  
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
9 
 
STUDY COMMITTEE MEMBERS 
COG RESEARCH COORDINATOR  
Kala Kamdar, MD 
Gisele B. Galit, MD 
Hematology/Oncology 
Children's Oncology Group  
Baylor College of Medicine 
Group Operations Center 
Pediatrics 
222 E. Huntington Drive. Suite 100 
6621 Fannin Street, CC1410.00 
Monrovia, CA 91016 
Houston, Texas  77030 
Phone: (626) 241-1570 
Phone:   (832) 824-4163 
Fax: 
(626) 445-4334 
Email:  kykamdar@txch.org  
E-mail: ggalit@childrensoncologygroup.org   
 
 
Lisa Giulino Roth, MD 
COG PROTOCOL COORDINATOR 
Hematology/Oncology 
Jeannette Cassar 
Weill Medical College of Cornell University 
Children's Oncology Group  
Pediatrics 
Group Operations Center 
1300 York Ave. C406 
222 E. Huntington Drive, Suite 100 
New York, NY 10065 
Monrovia, CA 91016 
Phone:   (212) 746-6948 
Phone: (626) 241-1532  
Email:  giulinol@mskcc.org  
Fax: 
(626) 445-4334  
 
E-mail: jcassar@childrensoncologygroup.org 
Sabrina Whitley Wigginton, BSN, RN, CPON 
 
Clinical Research Associates  
 
Children’s Hospital-King's Daughters  
 
Hematology/Oncology  
 
601 Children's Lane 
 
Norfolk, VA 23507 
 
Phone: (757) 668-7909  
 
Fax: 
(757) 668-9782  
 
E-mail: Sabrina.Wigginton@chkd.org   
 
 
 
Catherine Mary Bollard, MD 
 
Cellular Therapy 
 
Children’s National Medical Center 
 
Center for Cancer and Blood Disorders 
 
111 Michigan Avenue NW 
 
5th Floor Main, Suite 5200, Room 5207 
Brentuximab Vedotin 
NSC#749710  
Washington, DC 20010 
Crizotinib (Xalkori) 
NSC#749005   /Exempt 
Phone: (202) 476-4776 
Cyclophosphamide (Cytoxan) 
NSC# 26271    /Exempt 
Fax: 
(202) 476-5685 
Cytarabine  
NSC# 63878    /Exempt 
Email: cbollard@childrensnational.org  
Dexamethasone (Decadron) 
NSC# 34521    /Exempt 
 
Doxorubicin (Adriamycin)  
NSC# 123127  /Exempt 
Rodney R. Miles, MD PhD 
Etoposide  
NSC# 141540  /Exempt 
Pathology 
Filgrastrim (GCSF)  
NSC# 614629  /Exempt 
Primary Children's Hospital 
Hydrocortisone  
NSC# 010483  /Exempt 
Department of Pathology 
Ifosfamide  
NSC# 109724  /Exempt 
15 N. Medical Drive East, JMRB 2100 
Leucovorin  
NSC# 003590  /Exempt 
Salt Lake City, UT 84112-0565 
Mesna  
NSC# 113891  /Exempt 
Phone: (801) 584-5240 
Methotrexate 
NSC# 000740  /Exempt 
Fax: 
(801) 584-5124 
Pegfligrastim 
NSC# 725961  /Exempt 
Email: rodney.miles@path.utah.edu  
 
 
 
 
 
IND SPONSORS: NCI 
 
SEE SECTION 13 FOR SPECIMEN SHIPPING ADDRESSES 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
10 
 
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 
Despite numerous treatment strategies over the last 20 years failure rates remain 25-30% for pediatric 
anaplastic large cell lymphoma (ALCL). Two novel agents that have demonstrated high response rates as 
single agents in ALCL will be studied in this trial. Brentuximab vedotin (previously known as SGN35; 
currently marketed under the brand name Adcetris) is an antibody-drug conjugate containing an anti-CD30 
monoclonal antibody linked to a tubulin inhibitor (monomethylauristatin E). After binding CD30, a 
transmembrane receptor expressed on all ALCLs, brentuximab vedotin is internalized and the drug is 
released into the cytoplasm where it causes cell cycle arrest and apoptosis. Tubulin inhibitors are active 
agents in ALCL as evidenced by responses using vincristine and vinblastine. The response rate of 
brentuximab vedotin in patients with relapsed/refractory ALCL is impressive and the FDA has approved 
brentuximab vedotin for the treatment of patients with ALCL that have failed one line of therapy. Crizotinib 
is an orally bioavailable small molecule inhibitor of receptor tyrosine kinases including anaplastic large cell 
lymphoma kinase (ALK). ALK plays a central role in the pathogenesis of ALCL due to a chromosomal 
translocation that results in expression of an oncogenic kinase fusion protein. Crizotinib inhibits ALK 
phosphorylation resulting in antitumor activity. Crizotinib has also shown impressive response rates in 
patients with refractory/relapsed ALK positive ALCL. 
 
The primary aim of this pilot phase II study is to determine the toxicity and efficacy of the addition of two 
novel agents (brentuximab vedotin or crizotinib) to standard chemotherapy (best arm of ALCL99) in 
children with newly diagnosed ALCL. In this protocol, patients with newly diagnosed ALCL will be 
randomized to receive standard chemotherapy plus brentuximab vedotin (Arm BV) or standard 
chemotherapy plus crizotinib (Arm CZ). All patients will initially receive a 5 day prophase followed by 6 
cycles of chemotherapy. The novel agent (either brentuximab vedotin or crizotinib) will start with Cycle 1 
and be given in all 6 cycles. Each cycle lasts 21 days with the total therapy lasting approximately 19 weeks. 
Each arm will be evaluated for toxicity. Each arm will independently be evaluated for differences in EFS 
compared to historical data for ALCL99. A secondary aim of the trial will be to determine if minimal 
disease at diagnosis and/or minimal residual disease during treatment can identify patients at high risk of 
recurrence. Minimal disseminated disease (MDD) and minimal residual disease (MRD) will be measured 
using peripheral blood at 3 separate time points (diagnosis, after prophase, and after Cycle 1). The results 
from this pilot phase II study will provide necessary information to incorporate these novel agents into 
future trials and potentially improve the treatment of children with ALCL. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
11 
 
EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm BV 
Prophase 
Chemotherapy 
Days 1-5* 
Chemotherapy + BV 
Cycles 1-2* 
Study Entry * 
Arm CZ 
Chemotherapy + CZ 
Cycles 1-2* 
Prophase 
Chemotherapy 
Days 1-5* 
CR, CRU, PR, SD 
^Arm BV = Chemotherapy (6 cycles) + Brentuximab Vedotin Day 1 of each cycle 
^Arm CZ = Chemotherapy (6 cycles) + Crizotinib Days 1-21 of each cycle 
CR=Complete response/ CRU= Complete Response Unconfirmed /PR= Partial Response/ SD=Stable Disease/ PD=Progressive Disease. See Section 10.3 
Cycles 1, 3, 5 = Course A / Cycles 2, 4, 6 = Course B 
*MDD/MRD  
Collected at 3 time points: 
1) Baseline (prior to therapy) 
2) Day 6 (end of prophase and before 
Cycle #1) 
3) End of Cycle #1 
Prophase 
Cyclophosphamide Days 1-2 
Dexamethasone Days 1-5 
ITT: Day 1 
Course A (Cycles 1, 3, 5) 
Dexamethasone Days 1-5 
Ifosfamide Days 1-5 
Methotrexate Day 1 
Etoposide Days 4-5 
Cytarabine Days 4-5 
Course B (Cycles 2, 4, 6) 
Dexamethasone Days 1-5 
Methotrexate Day 1 
Cyclophosphamide Days 1-5 
Doxorubicin Days 4-5 
Chemotherapy + CZ 
Cycles 3-4 
^Chemotherapy + CZ 
Cycles 5-6 
^Chemotherapy + CZ 
Cycles 3-6 
Evaluation 
PR, SD 
Evaluation 
CR, CRU 
PD 
PD 
Off Protocol 
Therapy 
PD 
PD 
Evaluation 
^Chemotherapy + BV 
Cycles 5-6 
CR, CRU, PR, SD 
^Chemotherapy + BV 
Cycles 3-6 
CR, CRU 
PR, SD 
Evaluation
Chemotherapy + BV 
Cycles 3-4 
Is BSA < 0.9 m2?
No 
Randomization 
Yes 
Non-random Assignment  


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
12 
 
 
1.0 
GOALS AND OBEJCTIVES 
 
1.1 
Primary Aims 
1.1.1 
Tolerability 
To determine the tolerability of brentuximab vedotin given in combination with 
standard chemotherapy (ALCL99) and to determine the tolerability of crizotinib 
given in combination with chemotherapy (ALCL99). 
 
1.1.2 
Event Free Survival 
To estimate the Event Free Survival (EFS) of Arm BV and Arm CZ and contrast 
these to historical control data. 
 
1.2 
Secondary Aim 
1.2.1 
MDD/MRD 
To determine the prognostic significance of minimal disseminated disease (MDD) 
at diagnosis and minimal residual disease (MRD) as measured by RT- polymerase 
chain reaction (PCR) in peripheral blood. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
Anaplastic large cell lymphoma (ALCL) is a distinct form of non-Hodgkin lymphoma 
(NHL) which accounts for 10-15% of all childhood lymphomas.1,2 First described in 1985 
by Stein et al.,3 ALCL is a T or null cell lymphoma characterized by the malignant cell 
expression of CD30 (Ki-1). Despite numerous treatment strategies, EFS remains around 
70%.2,4-10 
Protocol 
Stratification 
Number 
Duration (months) 
EFS 
HM 89 / 91 
None 
82 
8 
66% 
NHL-BFM 90 
Disease Stage 
89 
5 
76% 
ALCL 99 
Clinical Features 
352 
5 
73% 
UKCCSG 
Disease Stage 
72 
7-8 
59% 
POG 9315 
None 
86 
12 
72% 
CCG 5941 
None 
86 
12 
68% 
LSA2-L2 modified 
None 
34 
24 
65% 
 
ANHL0131 tested the substitution of vinblastine for vincristine in children with ALCL 
when given with APO (Doxorubicin, Prednisone, and Vincristine) chemotherapy (52 
weeks of therapy). Results showed similar EFS to other studies and no benefit to the 
patients receiving the additional vinblastine (3 yr EFS of 75% for APO vs. 80% for APV, 
p = 0.73). The international ALCL99 trial used chemotherapy based on BFM-NHL-90 
(duration of 4 months). The first randomization compared methotrexate 1 g/m2 
administered over 24 hours with intrathecal chemotherapy throughout therapy versus 
methotrexate 3 g/m2 administered over 3 hours with intrathecal chemotherapy only in 
prophase of therapy. Overall, 352 patients were randomized. While the 2 year EFS (73% 
versus 75%) did not differ between the 2 arms, the toxicity from the methotrexate 
administered over 3 hours was significantly less and the 2 CNS relapses both occurred on 
the arm with 1 g/m2 and intrathecal chemotherapy.5 Therefore, it is now considered 
standard of care when using the ALCL99 regimen to use 3 g/m2 of methotrexate over 
3 hours and intrathecal chemotherapy only in the prophase. The second randomization was 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
13 
 
for patients with clinically “high-risk features”, i.e. involvement of skin, mediastinum, 
liver, lung and/or spleen. Patients were randomized to standard chemotherapy ± vinblastine 
weekly as maintenance for a total duration of 1 year of therapy. While vinblastine delayed 
relapses, there was no difference in the 2 year EFS (73% versus 70%) in the 217 
randomized patients.10 Thus, the ALCL99 trial demonstrated a failure rate of 
approximately 30%, all but initial intrathecal chemotherapy can safely be omitted when 
using 3 g/m2 of methotrexate administered over 3 hours, and the addition of vinblastine 
maintenance did not improve EFS. 
 
While studies have used a wide range of chemotherapy strategies, no intervention has been 
able to improve on the approximate failure rate of 25%-30% that exists regardless of 
treatment strategy. The addition of vinblastine, either with chemotherapy or as single agent 
in maintenance, failed to show any improvement in EFS in both the ANHL0131 and 
ALCL99 trials. CCG 5941 showed no advantage to intensifying multi-agent chemotherapy 
given over 11 months. Intensification with intermediate dose methotrexate and high dose 
cytarabine on an APO backbone did not improve outcome (POG 9315). Intensification 
with high dose cytarabine, etoposide and methotrexate did not improve outcome in high 
risk patients (NHL-BFM 95). The Italian group (AIEOP) was unable to demonstrate benefit 
of longer duration of therapy using a modified LSA2-L2 acute leukemia regimen (duration 
2 years; 65% EFS). 
 
In addition, progression while receiving chemotherapy portends a very poor prognosis in 
children with ALCL, with only 25% of patients who progress on therapy expected to 
survive even with aggressive salvage therapy, including allogeneic transplant.11,12 
Therefore, interventions that prevent relapse, especially on-therapy progression of disease, 
will have the greatest impact on overall survival and toxicity. 
 
2.2 
Brentuximab vedotin Background 
The CD30 antigen is a transmembrane glycoprotein receptor that is expressed on all 
systemic ALCL in children.13 Brentuximab vedotin is a CD30 targeted antibody (cAC10) 
conjugated to monomethyl auristatin E (MMAE). Brentuximab vedotin binds to CD30, 
becomes internalized, and then releases MMAE that causes apoptosis as an antitubulin 
agent. 
 
Preclinical data demonstrated that MMAE binds to the same site on tubulin as vinblastine. 
Using mouse xenografts of a Hodgkin Lymphoma (HL), which also highly expresses 
CD30, cell line, Alley et al. were able to demonstrate that brentuximab vedotin had a peak 
tumor concentration 10-30 fold greater than MMAE or vinblastine delivered in a non-
targeted fashion, or systemic administration.14 In addition, over a three day period, the 
tumor exposure to the anti-tubulin agent after brentuximab vedotin was 5-10 fold higher 
than when given as a non-targeted agent. 
 
There have been two phase I studies of brentuximab vedotin involving patients with 
relapsed HL or ALCL.15-17 In the first phase I study, brentuximab vedotin was given every 
3 weeks. Of the 45 patients enrolled, 33 (73%) had previously received a stem cell 
transplant. Despite this high amount of pretreatment, toxicity was tolerable. The most 
common toxicities were fatigue (40%), pyrexia (33%), peripheral neuropathy (31%), 
diarrhea (22%), nausea (22%), headache (20%), and vomiting (20%). The vast majority of 
these toxicities were Grade 1 or 2. In this study, the dose limiting toxicities were prostatitis, 
hyperglycemia, and unrelated acute renal failure. The dose recommended for future studies 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
14 
 
was 1.8 mg/kg every 3 weeks. In addition, brentuximab vedotin was determined to be 
minimally immunogenic. Of the 45 patients treated, only 2 developed low levels of human 
anti-brentuximab vedotin antibody which showed no effect on clearance of the drug. The 
second phase I study gave brentuximab vedotin weekly with similar toxicities: fatigue 
(24%), peripheral neuropathy (18%), nausea (26%), neutropenia (18%), and 
hyperglycemia (12%). In these phase I trials, 6/7 patients with ALCL had a complete 
response and 1 had stable disease. 
 
A phase II multicenter trial using brentuximab vedotin 1.8 mg/kg every 3 weeks for 
patients over 12 years of age with relapsed or refractory ALCL has recently been 
completed.18,19 Brentuximab vedotin was administered over 30 minutes as an outpatient 
every 3 weeks. A total of 58 patients were enrolled with an overall response rate of 86% 
(53% CR, 33% PR) and 97% of patients demonstrated tumor reduction. There was no 
difference between those patients who had ALK positive versus ALK negative ALCL. The 
responses have been durable, with the median duration of CR for patients off treatment not 
having been reached. Adverse events were manageable with a toxicity profile similar to 
phase I study. The most common toxicities were nausea (38%), peripheral sensory 
neuropathy (38%), fatigue (34%), pyrexia (33%), diarrhea (29%), and neutropenia (21%). 
Grade 3 and 4 toxicities were rare (Grade 3/4: neutropenia 12%/9%, peripheral sensory 
neuropathy 10%/0%, thrombocytopenia 9%/5%, anemia 7%/0%). Because brentuximab 
vedotin is an anti-tubulin agent, toxicities involving neuropathy were closely monitored. 
Grade 1/2, 3, or 4 toxicity rates included peripheral sensory neuropathy (28%, 10%, and 
0% respectively), paresthesias (5%, 0%, and 0%) and peripheral motor neuropathy (3%, 
2%, and 0%). Most patients (79%) showed improvement or resolution of their symptoms 
over time. In addition, a phase II multicenter trial using brentuximab vedotin 1.8 mg/kg 
every 3 weeks for patients over 12 years of age with relapsed or refractory Hodgkin 
Lymphoma enrolled 102 patients and had a similar toxicity profile. 
 
Brentuximab vedotin has recently been combined with chemotherapy for adults with newly 
diagnosed Hodgkin lymphoma.20 Brentuximab vedotin was given in combination with 
ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) to 25 patients and in 
combination with AVD (no bleomycin) to 19 patients. In the ABVD cohort, 10 of 
25 patients developed pulmonary toxicity that prompted the change to AVD. Seven of the 
10 patients who developed pulmonary toxicity went on to receive brentuximab vedotin and 
AVD without any further pulmonary toxicity. None of the patients in the AVD cohort have 
experienced pulmonary toxicity. Of note, there was minimal lung toxicity in the phase II 
single agent studies that included many patients who had lymphoma involvement of the 
lungs, suggesting that the pulmonary toxicity seen on this study was a result of the 
combination of brentuximab vedotin with bleomycin. Overall, 44 patients received 
brentuximab vedotin with chemotherapy and there were 0 DLTs observed concluding that 
a dose of 1.2 mg/kg every 2 weeks can be given with AVD. The most common Grade 3+ 
toxicities occurring in the 44 patients were neutropenia (77%), anemia (14%), fever and 
neutropenia (11%), pulmonary toxicity (11%), dypsnea (9%), and syncope (9%). Of note, 
although 52% of patients had Grade 1 or 2 peripheral neuropathy, no patient had Grade 3 
or 4 neuropathy. 
 
Brentuximab vedotin has also been given with CH-P (cyclophosphamide, doxorubicin, 
prednisone) chemotherapy to newly diagnosed patients with ALCL. Patients were given 
brentuximab vedotin at 1.8 mg/kg every 3 weeks with CH-P therapy. De-escalation was 
not required as none of the initial six patients enrolled on this arm experienced a Dose 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
15 
 
Limiting Toxicities (DLTs) defined as greater than 7 day delay in chemotherapy 
administration. Of the 20 total patients who have received concurrent brentuximab and 
CH-P, the most common side effects have been rash (10%), fever neutropenia (20%), and 
nausea (25%). The authors conclude that the recommended dose for brentuximab with 
CH-P chemotherapy is 1.8 mg/kg [personal communication, T-cell Lymphoma Forum Jan. 
2012]. 
 
In addition, brentuximab vedotin given in combination with gemcitabine (AHOD1221) is 
currently open to enrollment and will provide additional data as patients receive therapy. 
 
2.3 
Crizotinib Background 
Pediatric ALCL is characterized by having the vast majority of cases express anaplastic 
large cell lymphoma kinase (ALK).21 ALK is a gene found on chromosome 2 and 
translocations affecting the ALK gene can result in the expression of oncogenic fusion 
proteins. The ALK protein is a fusion protein produced by a genetic translocation most 
commonly t(2;5) involving the ALK gene on chromosome 2 and the nucleophosmine 
(NPM) gene on chromosome 5. The formation of ALK fusion proteins results in activation 
and dysregulation of the gene’s expression and signaling which can contribute to increased 
cell proliferation and survival in tumors expressing these proteins. The ALK protein has 
been implicated in the pathogenesis of pediatric ALCL.22  
 
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK and Hepatocyte 
Growth Factor Receptor (HGFR, c-Met). Crizotinib inhibits ALK phosphorylation 
resulting in antitumor activity. Crizotinib was found to potently inhibit cell proliferation in 
ALK positive ALCL cells but not ALK negative cells.23 Crizotinib has also been shown to 
have antitumor activity in mice expressing tumors with the ALK fusion protein. 
 
Crizotinib has been evaluated in two single-arm adult clinical trials for the treatment of 
locally advanced or metastatic ALK-positive NSCLC.24 Among the 397 patients for whom 
information on deaths and serious adverse reactions are available, the most common 
adverse reactions (≥ 25%) were vision disorder, nausea, diarrhea, vomiting, edema, and 
constipation. Grade 3-4 adverse reactions in at least 4% of patients in both studies included 
increased ALT and neutropenia. The rates of treatment-related adverse events resulting in 
permanent discontinuation were 6% in one study and 3% in the other. Serious adverse 
events in greater than or equal to 2% of patients included pneumonia, dyspnea, and 
pulmonary embolism. 
 
Crizotinib is also effective in treating patients with relapsed ALCL. A report from the New 
England Journal of Medicine reported 2 adult patients with recurrent ALK positive ALCL 
who achieved CRs after receiving single agent crizotinib.25 These authors updated their 
experience at the International Lymphoma Meeting in June 2011 reporting 2 additional 
patients with responses of CR and PR demonstrating clear activity in ALK positive ALCL. 
 
ADVL0912 is an ongoing phase I1/II study of crizotinib in children with 
Relapsed/Refractory Solid Tumors, Primary CNS Tumors, and Anaplastic Large Cell 
Lymphoma. Seventy subjects have been enrolled on the pediatric phase 1 study of 
crizotinib including 8 with ALCL.26 The toxicity profile overall has been good with DLT 
reached in 2/7 patients at 215 mg/m2/dose BID and 1/6 at 365 mg/m2/dose BID. A separate 
stratum of 18 patients with known ALK mutations were enrolled at 1 dose level lower than 
A1 stratum. One patient experienced a DLT of Grade 4 neutropenia. Eight patients with 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
16 
 
ALCL have received crizotinib (6 at 165 mg/m2/dose BID which is roughly equivalent to 
the dose used in the adult studies and 2 at 280 mg/m2/dose BID). Of the 8 patients, there 
have been 7 CRs for a complete response rate of 88%. Many of these responses are ongoing 
as the patients are continuing to receive medication [personal communication- Y. Mosse]. 
 
ADVL1212 is a recently opened study evaluating the safety and tolerability of crizotinib 
administered in combination with topotecan and cyclophosphamide or vincristine and 
doxorubicin. As this study accrues, more information will be available to support the safety 
of combination chemotherapy with crizotinib. 
 
2.4 
Study Rationale 
 
2.4.1 
Rationale for ALCL99 
Though APO regimen can be given as outpatient therapy, it is 52 weeks in 
duration. While ALCL99 therapy usually requires hospitalization, the duration is 
only 19 weeks. The APO regimen gives doxorubicin at a cumulative dose of 
300 mg/m2; whereas ALCL99 gives 150 mg/m2 total of doxorubicin. Additionally, 
the ALCL99 study demonstrated that giving methotrexate (3 g/m2 over 3 hours) 
resulted in less toxicity and no increased risk of CNS relapses, than methotrexate 
1 g/m2 given over 1 hour plus intrathecal therapy. Lastly, the BFM finding of 
prognostic value of minimal disease and minimal residual disease was a 
retrospective, subset analysis of patients on BFM-NHL-90 and ALCL99. By using 
the ALCL99 for the backbone of chemotherapy, we will reduce the exposure to 
anthracycline, reduce intrathecal chemotherapy, reduce time in treatment, have the 
ability to compare results directly to the largest trial in pediatric ALCL, and have 
the opportunity to confirm or dispute the BFM findings regarding minimal disease 
and minimal residual disease in a prospective fashion.  
 
2.4.2 
Rationale for eligibility 
Patients must have disease that is both CD30 positive and ALK positive since these 
are the targets of brentuximab vedotin and crizotinib respectively. Patients with 
skin disease only will not be eligible as skin only disease exhibits very different 
characteristics than systemic disease. Since patients with central nervous system 
disease are rare and we do not want to cloud any neurological toxicity associated 
with either drug, patients with CNS disease will not be eligible. Patients with Stage 
II, III, and IV disease will be eligible. Attarbaschi et al. demonstrated that patients 
with Stage II disease have similar EFS and OS as more advanced stage disease 
using ALCL-99 therapy.27 In addition, in a multivariate analysis of 225 children 
with ALCL of all stages, stage was not predictive of outcome.28 While recent COG 
trials have not included Stage II patients, there are no data that Stage II patients 
have an outcome different than patients with higher stage disease. 
 
2.4.3 
Rationale for brentuximab vedotin and crizotinib 
Since all cases of ALCL express CD-30, this is an ideal target for directed therapy. 
Brentuximab vedotin is a unique antibody drug conjugate which delivers a tubulin 
inhibitor directly to the tumor cells. Tubulin inhibitors are active agents in ALCL 
as evidenced by responses using vincristine and vinblastine. The response rate 
using brentuximab vedotin as a single agent for patients with relapsed/refractory 
ALCL is impressive. We hypothesize that the toxicity will be tolerable and that 
this agent will be active and this agent will advance into larger, more definitive 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
17 
 
studies. We plan to utilize a dose of 1.8 mg/kg every 3 weeks which is the dose 
utilized in the phase II trials for ALCL. This dose gives similar exposure to the 
1.2 mg/kg every 2 weeks that was tolerable in combination with chemotherapy in 
the upfront Hodgkin lymphoma trial and is the current dose being evaluated with 
CH-P therapy in upfront ALCL. There will be a de-escalation of the dose should 
patients experience delays in chemotherapy as the DLT. 
 
Because pediatric ALCL is characterized by having the vast majority of cases 
express ALK and the ALK protein is postulated to be the oncogenic drive in the 
pathogenesis for pediatric ALCL, this is an ideal target for treatment. The rationale 
for the use of inhibitors directed toward oncogenic tyrosine kinases that are 
genetically altered is supported by many recent examples such as imatinib in 
gastrointestinal stromal tumors with mutant c-Kit or chronic myelogenous 
leukemia with BCR-Abl gene translocations. Moreover, AALL0031 demonstrated 
remarkable clinical efficacy when combining a targeted tyrosine kinase inhibitor 
(imatinib) with standard chemotherapy for Ph+ ALL. We hypothesize that the 
toxicity will be tolerable and that this agent will be active and this agent will 
advance into larger, more definitive studies. We plan to use the 165 mg/m2/dose 
BID dose as this has shown reasonable toxicity in ADVL0912 with excellent 
response rates. 
 
Despite numerous treatment strategies over the last 20 years, failure rates remain 
25-30% for pediatric ALCL. This study proposes to randomize patients to 2 arms. 
Arm BV will add brentuximab vedotin to standard chemotherapy per ALCL99 
(3 g/m2 methotrexate and prophase intrathecal chemotherapy only). Arm CZ will 
add crizotinib to standard chemotherapy per ALCL99 (3 g/m2 methotrexate and 
prophase intrathecal chemotherapy only). This design will allow for determination 
of toxicity of brentuximab vedotin and crizotinib with chemotherapy, as well as 
provide preliminary information on EFS when compared to historical controls. The 
results of this study will provide all the necessary information to design more 
definitive studies testing the benefit of novel agents in improving the outcome of 
children with ALCL. 
 
2.5 
Biology 
 
2.5.1 
Minimal Disseminated Disease (MDD) / Minimal Residual Disease (MRD) 
Clinical and histological characteristics have limited prognostic value in children 
with ALCL. As the majority of ALCL in children possess a genetic translocation 
involving the anaplastic large cell lymphoma kinase (ALK) gene,21 a polymerase 
chain reaction (PCR) for NPM-ALK provides an ideal platform to assess minimal 
disease. In a report from Damm-Welk et al., minimal disease in bone marrow or 
peripheral blood found by PCR at diagnosis identified a group of patients with a 
high incidence of relapse.29 Overall there was a cumulative incidence of relapse of 
50% for the 38 patients who were PCR positive and a cumulative incidence of 
relapse of 15% for the 42 patients who were PCR negative (p < 0.001). In 
multivariate analysis, the relative risk of relapse for patients with quantitative PCR 
positive bone marrow was 4.74 (p=0.006) but only 1.67 (p = 0.32) for the clinical 
risk features previously considered high risk by some groups.28,29 In multivariate 
analysis, the relative risk of relapse for patients with qualitative PCR positive bone 
marrow was 3.47 (p = 0.028). Although fewer samples were tested in peripheral 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
18 
 
blood, there was a high concordance rate (Spearman correlation coefficient = 0.84; 
p < .001) between the bone marrow PCR results and the peripheral blood PCR 
results. Overall, both quantitative and qualitative PCR in either peripheral blood 
or bone marrow identified high risk patients in this small selection of patients. 
 
Since minimal disease at diagnosis may be prognostic, it follows that minimal 
residual disease during therapy may also hold prognostic significance. Defining 
MRD as qualitative PCR positivity, the same researchers who studied minimal 
disease at diagnosis, examined minimal residual disease at Day 6 and after course 
1, in a very limited number of samples. Minimal residual disease at both time 
points identified patients at higher risk for relapse (personal communication- W. 
Woessman). We hypothesize that MDD/MRD will be of great importance in the 
future of treatment for ALCL allowing us to identify patients early in treatment 
who have a high risk of recurrence. 
 
2.6 
Thromboembolic Background 
Thromboembolic adverse events, which are frequently multifactorial in causality, have 
been reported with many of the chemotherapy agents given on ANHL12P1 including 
crizotinib and brentuximab vedotin. Amendment #5 modified the ANHL12P1 protocol and 
consent document to reflect the potential risk of thromboembolic events. Further evaluation 
of the thromboembolic events on this trial has been undertaken. Briefly, there have been 
15 thromboembolic events on ANHL12P1 as of September 27, 2017 (4 subjects had a 
pulmonary embolism (2 of 4 known to be catheter-related) and 11 had a catheter-related 
clot). Nine of the catheter-related thromboses (6 in Arm CZ and 3 in Arm BV) have been 
asymptomatic and discovered on routine tests (echo or CT) for other purposes. One 
catheter-related thrombosis (Arm CZ) was symptomatic with neck discomfort from the 
central line migrating position into the neck and another (Arm BV) was symptomatic with 
arm swelling. The incidence point estimate for a Grade 2+ Adverse Event of a catheter-
related thrombosis is 17.1% (95% CI 7.2%–32.1%) on Arm CZ and 6.0% (95% CI 1.7%–
14.6%) on Arm BV with the larger CI for Arm CZ mostly due to fewer patients enrolled 
to date on that arm. All 4 pulmonary emboli occurred on Arm CZ (giving an incidence 
point estimate of 9.8%; 95% CI 2.7%–23.1%). No deaths have occurred due to 
thromboembolic events. The increased risk of thromboembolic events in Arm CZ has 
resulted in the requirement to use anticoagulation for prophylaxis as of Amendment #6A. 
 
 
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 Patient Registry module in OPEN 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. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
19 
 
In order for an institution to maintain COG membership requirements, every patient 
with a known or suspected neoplasm needs to be offered participation in APEC14B1, 
Project:EveryChild A Registry, Eligibility Screening, Biology and Outcome Study.  
 
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 III for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (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 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating 
organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix III.  
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. For sites using the CIRB, IRB approval information is 
received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally.  The 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
20 
 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in 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 
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://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the lead 
protocol organization (LPO) or participating organization roster. Registrars must 
hold a minimum of an AP registration type. If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
 
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. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval. If a DTL is required for the study, 
the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
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. 
 
3.1.4 
Timing 
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 a Phase II study 
prior to study enrollment will be considered ineligible.  
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
21 
 
 
3.1.5 
Randomization 
Randomization will take place at the time a patient is enrolled via OPEN. 
Eligible patients will be stratified as follows: 
• 
Stratum 1: Patients with BSA ≥ 0.9 m2  
• 
Stratum 2: Patients with BSA < 0.9 m2  
 
Eligible patients in Stratum 1 will be randomized (1:1) to Arm BV or Arm CZ. 
Eligible patients in Stratum 2 will be non-randomly assigned to Arm BV because 
crizotinib is only available in certain strengths. 
 
3.1.5.1 Two exceptions to randomization: 
1) If one arm is temporarily closed, patients will be non-randomly assigned 
to the other arm.  
2) If Arm BV is temporarily closed and the patient is < 0.9 m2, then the 
patient is not eligible for the study. 
 
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 that will serve as the source document for 
verification at the time of audit. 
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy. Imaging studies, if applicable, must be obtained 
within 2 weeks prior to start of protocol therapy (repeat the tumor imaging if 
necessary). 
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
INCLUSION CRITERIA 
 
3.2.1 
Age 
Patient must be < 22 years of age at the time of study enrollment. 
 
3.2.2 
Diagnosis 
• Newly diagnosed patients with histologically proven ALCL (ICD-0 code: 9714/3). 
• Disease must be CD30 positive.  
• Disease must be ALK positive (defined by local institutional standards).  
• Patients must have Stage II, III, or IV disease (See Appendix I for staging). 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
22 
 
 
3.2.3 
Life Expectancy 
Patients must have a life expectancy of  8 weeks. 
 
3.2.4 
Organ Function Requirements 
3.2.4.1 
Adequate Liver Function Defined As: 
• 
Total bilirubin  1.5 x upper limit of normal (ULN) for age. 
• 
ALT (SGPT) < 2.5 x upper limit of normal (ULN) for age. For the 
purpose of this study, the ULN for ALT is 45 U/L. 
• 
If the lab abnormality is thought to be due to the lymphoma the 
patient is eligible and dose adjustments should be made (See 
Section 5.0). 
 
3.2.4.2 
Adequate Cardiac Function Defined As: 
• 
Shortening fraction of  27% by echocardiogram, or 
• 
Ejection fraction of ≥ 50% by radionuclide angiogram. 
 
3.2.4.3 
Adequate Pulmonary Function Defined As: 
• 
Patients with a history of pulmonary dysfunction must have no 
evidence of dyspnea at rest, no exercise intolerance due to 
pulmonary insufficiency, and a pulse oximetry > 92% while 
breathing room air unless current dysfunction is due to the 
lymphoma in which case the patient is eligible. 
 
3.2.5 
Exclusion Criteria 
3.2.5.1 
Patients with CNS disease are not eligible. 
 
3.2.5.2 
Patients with disease limited to the skin are not eligible, regardless of 
how wide-spread. 
 
3.2.5.3 
Patients with Stage I disease are not eligible.  
 
3.2.5.4 
Patients who have received any prior cytotoxic chemotherapy for the 
current diagnosis of ALCL or any cancer diagnosed previously are not 
eligible.  
 
3.2.5.5 
Previous steroid treatment and/or radiation treatment is not allowed 
unless it is for the emergent management of a mediastinal mass. 
Emergent steroid treatment and/or radiation treatment should stop once 
protocol therapy is initiated. 
 
3.2.5.6 
Intrathecal chemotherapy prior to enrollment is allowed for the current 
diagnosis of ALCL as long as adequate CSF is obtained prior to 
administration of the intrathecal chemotherapy and subsequently 
demonstrated to be negative for ALCL. (See Section 4.2) 
 
3.2.5.7 
Female patients who are pregnant are not eligible due to risks of fetal 
and teratogenic adverse events. Pregnancy tests must be obtained in girls 
who are post menarchal. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
23 
 
 
3.2.5.8 
Lactating females are not eligible unless they have agreed not to 
breastfeed their infants. 
 
3.2.5.9 
Sexually active patients of reproductive potential are not eligible unless 
they agree to use an effective contraceptive method for the duration of 
treatment and for 3 months after stopping treatment. 
 
3.2.5.10 Patients with Down syndrome are not eligible due to the amount of 
methotrexate and potential for side effects. 
 
3.2.5.11 Patients with an immunodeficiency that existed prior to diagnosis such 
as primary immunodeficiency syndromes or organ transplant recipients 
are not eligible.  
 
3.2.5.12 CYP3A4 Substrates with Narrow Therapeutic Indices: Patients 
chronically receiving medications known to be metabolized by CYP3A4 
and with narrow therapeutic indices including pimozide, aripiprazole, 
triazolam, ergotamine and halofantrine are not eligible. The topical use 
of these medications (if applicable) is allowed. See Appendix IV. 
 
3.2.5.13 CYP3A4 Inhibitors: Patients chronically receiving drugs that are known 
potent CYP3A4 inhibitors within 7 days prior to study enrollment, 
including but not limited to ketoconazole, itraconazole, clarithromycin, 
erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, delavirdine, 
nefazodone, diltiazem, verapamil, and grapefruit juice are not eligible. 
The topical use of these medications (if applicable), e.g. 2% 
ketoconazole cream, is allowed. See Appendix IV. 
 
3.2.5.14 CYP3A4 Inducers: Patients chronically receiving drugs that are known 
potent CYP3A4 inducers within 12 days prior to study enrollment, 
including but not limited to carbamazepine, phenobarbital, phenytoin, 
rifabutin, rifampin, ritonavir, and St. John’s wort are not eligible. The 
topical use of these medications (if applicable) is allowed. See 
Appendix IV. 
 
3.2.5.15 Patients that are known to be positive for HIV are not eligible. 
Note: Inclusion of HIV positive patients will be considered at a later 
date. 
 
3.2.5.16 Patients who weigh < 10 kg are not eligible.  
 
3.2.6 
Regulatory Requirements 
 
3.2.6.1 
All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.6.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
24 
 
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 
 
Eligible patients will be stratified as follows: 
• 
Stratum 1: Patients with BSA ≥ 0.9 m2  
• 
Stratum 2: Patients with BSA < 0.9 m2  
 
At study enrollment: 
• 
Eligible patients in Stratum 1 will be randomized (1:1) to Arm BV or Arm CZ. 
• 
Eligible patients in Stratum 2 will be non-randomly assigned to Arm BV because 
crizotinib is only available in certain strengths. 
 
Arm BV: Patients receive standard chemotherapy plus brentuximab vedotin. 
 
Arm CZ: Patients receive standard chemotherapy plus crizotinib. 
 
Two exceptions to randomization: 
1) If one arm is temporarily closed, patients will be non-randomly assigned to the other arm.  
2) If Arm BV is temporarily closed and the patient is < 0.9 m2, then the patient is not eligible 
for the study. 
 
All patients will receive a 5 day prophase followed by alternating Courses (A and B) 
administered every 21 days for a total of 6 cycles (3 cycles of Course A and 3 cycles of 
Course B). The study agents will begin on Day 1 of Cycle 1 following the prophase. Growth 
factors are not required but will be permitted as the standard chemotherapy backbone 
causes neutropenia and both brentuximab vedotin and crizotinib have been shown to cause 
neutropenia. If used, the use of growth factor should be reported. 
 
4.1.1 
Supportive Care Guidelines 
 
• 
Thromboembolic events are known side effects of chemotherapy and/or the 
presence of a central venous catheter. Many thromboembolic events have 
multifactorial causes. Whenever possible, treating physicians should make 
every attempt to eliminate additional risk factors such as tobacco use, 
dehydration, concomitant medications, etc. that increase the risk for 
thrombosis. 
 
• Tumor Lysis: Patients with massive tumor burden should be hydrated prior to 
initiation of chemotherapy and monitored for tumor lysis syndrome. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
25 
 
• Prophylactic anticoagulation is required for patients on Arm CZ due to the 
potential risk of thromboembolic events (see Section 2.6). Anticoagulation 
may be implemented according to each institution’s standard of care for 
prophylactic anticoagulation OR utilizing low molecular weight heparin with 
a goal Anti-Xa of 0.1-0.3 units/mL. More information can be found at: 
https://childrensoncologygroup.org/downloads/COG_SC_Thrombosis_Guide
line_Document.pdf.  
It is important to note potential drug interactions between the 
chemotherapeutic agents on Arm CZ and certain anticoagulation medications 
(including but not limited to warfarin, apixaban, and rivaroxaban). 
 
• Risk of bleeding secondary to chemotherapy induced thrombocytopenia 
should be minimized using platelet transfusions according to each institution’s 
standard of care for thrombocytopenic patients receiving anticoagulation. 
 
• Central venous line: Insertion of a central venous line is recommended prior 
to the administration of treatment. Two lumens are preferred for ease in 
chemotherapy administration. This may have to be delayed in the event of a 
large mediastinal mass, being a contraindication to surgery. 
 
• Mucositis: Mucositis is expected particularly after Course B (Cycles 2, 4, and 
6). Patients should be instructed on the importance of meticulous oral hygiene 
to reduce oral infections and prevent mucositis. 
 
• Anti-emetics: Anti-emetics should be given during each chemotherapy cycle. 
Steroids should not be used as anti-emetic therapy. 
 
• Pneumocystis jiroveci pneumonia prophylaxis: Appropriate prophylaxis 
should be given per institutional standards. 
 
For COG Supportive Care Guidelines see: 
https://childrensoncologygroup.org/cog-supportive-care-guidelines. 
 
4.1.2 
Concomitant Therapy Restrictions 
 
• Strong inducers or inhibitors of CYP3A enzymes should be avoided.  
 
• See Appendix IV for full list. 
 
• The metabolism of the two investigational agents (crizotinib and brentuximab 
vedotin) is predominantly mediated by the CYP3A isozymes. Co-
administration with drugs that are CYP3A inhibitors and inducers may change 
the plasma concentrations of crizotinib and/or brentuximab vedotin in humans. 
The chronic concurrent use of potent CYP3A inhibitors and potent CYP3A 
inducers (with the exception of protocol defined therapy) must be avoided until 
treatment discontinuation. The list of potent CYP3A4 inhibitors and inducers 
in Appendix IV should be avoided whenever possible, and therapeutic 
alternatives to these agents are recommended. Please see Appendix IV for a 
list of common substrates, inhibitors, and inducers of CYP3A4. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
26 
 
4.2 
Prophase (5 days) – Arms BV and CZ 
 
Intrathecal chemotherapy may be administered at the time of the diagnostic lumbar 
puncture prior to enrollment on study. No other chemotherapy should begin prior to 
enrollment. 
 
Peripheral blood for MDD/MRD should be drawn prior to beginning prophase. (Time 
point #1) 
 
Those patients with bulky disease may be at risk for metabolic problems associated 
with tumor lysis. Please use appropriate supportive care. 
 
Cyclophosphamide: IV over 15 - 30 minutes 
Days: 1 and 2 
Dose: 200 mg/m2/dose.  
 
May be administered with or without further dilution. To avoid hypotonic solution, 
reconstitute Cyclophosphamide with 0.9% NaCl to a final concentration of 20 mg/mL.  
 
Dexamethasone: PO (may administer IV if patient unable to take oral medications) 
Days: 1-5 
Dose: 5 mg/m2/dose once daily on days 1 and 2.  
          5 mg/m2/dose BID on days 3, 4, 5. 
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. 
Liquid preparations are also acceptable. Intravenous preparation may be used temporarily 
as needed. 
 
Intrathecal Triple Therapy (ITT): age appropriate dose (see below) 
Day 1 (may be administered during diagnostic lumbar puncture) 
Dose: 
 
Age (yrs) 
IT MTX 
IT HC  
IT ARAC 
  0-0.99  
 7.5 mg  
7.5 mg  
15 mg 
  1-1.99  
 8 mg  
8 mg 
 
16 mg 
  2-2.99  
 10 mg  
10 mg  
20 mg 
   ≥ 3 
 
 12 mg  
12 mg  
24 mg 
 
For IT administration, use preservative free formulation. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for the prophase (all Arms) is on the next page.  
 
Cycle 1 for both arms starts on Day 6 of the prophase (i.e., Day 6 of prophase is Day 1 of 
Cycle 1). 
 
Peripheral blood for minimal residual disease (MRD) should be drawn prior to 
beginning Cycle 1. (Time point #2) 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
27 
 
4.2.1 
Prophase (5 days) Arm BV and CZ 
____________________           ___________ 
Patient COG ID number                    DOB 
Prophase lasts 5 days.  This Therapy Delivery Map is on one (1) page. 
 
Prophase  Ht _________cm   Wt _________kg 
BSA _________m2   Growth Factor Used?   Y/N? 
 
*See Section 7.1. for the full list of baseline studies that need to be done prior to starting protocol therapy, including blood for 
MRD. The studies listed on this TDM need to be completed prior to prophase. 
See Section 5.0 for Dose Modifications for Toxicities and the COG website posted materials for Supportive Care Guidelines. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Cyclophosphamide 
(CPM) 
IV over 
15 - 30 
minutes 
200 mg/m2/dose 
1& 2 
 
a.History 
b.Physical Exam 
(weekly) 
c.CBC/diff/plts 
(weekly) 
d.Electrolytes (weekly) 
e.Performance Status 
f.Cr,Bilirubin,AST,ALT 
g.Urinalysis 
h.Blood for MRD 
 
 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE. (See Section 
7.1.) 
Dexamethasone 
(DEX) 
PO 
5 mg/m2/dose once a day on days 1 and 2 
5 mg/m2/dose  BID on days 3-5 
 
 
Once daily on 
Days 1 & 2   
 
BID Days 3-5 
May give IV if 
unable to take 
PO. 
Intrathecal Triple 
Therapy (ITT): 
 
Methotrexate 
(IT MTX) 
Hydrocortisone  
(IT HC) 
Cytarabine  
(IT ARAC) 
IT 
Age(yrs)    Dose 
 
0-0.99  MTX: 7.5mg,  HC: 7.5mg,  ARAC: 15mg 
1-1.99  MTX: 8mg,     HC: 8mg,     ARAC: 16mg 
2-2.99  MTX: 10mg,  HC: 10mg,   ARAC: 20mg 
≥ 3       MTX: 12mg,  HC: 12mg,   ARAC: 24mg 
Day 1 
Note age-based 
dosing. 
Date Due 
Date Given 
Day 
CPM 
____mg 
DEX 
____mg 
____mg$ 
$ (BID Days 3-5)  
ITT 
____mg   (IT MTX) 
____mg   (IT HC) 
____mg   (IT ARAC) 
Studies 
Comments 
Enter calculated dose above and actual dose administered below. 
 
 
1 
____mg 
____mg 
____mg    (IT MTX) 
____mg    (IT HC) 
____mg    (IT ARAC) 
a – h* 
 
 
 
2 
____mg 
____mg 
 
 
 
 
 
3 
 
_____mg _____mg$ 
 
 
 
 
 
4 
 
_____mg _____mg$ 
 
 
 
 
 
5 
 
_____mg _____mg$ 
 
 
 
 
 
6/1 
 
 
 
h 
MRD blood draw is Day 
6, before Cycle 1. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
28 
 
4.3 
Course A (21 days) – Arm BV (Cycles 1, 3 and 5) 
Peripheral blood for minimal residual disease (MRD) should be drawn prior to 
beginning Cycle 1. (Time point #2) 
 
Cycle 1 should begin on Day 6 of the prophase. Cycles 3 and 5 should begin on Day 22 of 
the previous cycle when peripheral counts have recovered with ANC ≥ 500/mm3 and 
platelets ≥ 50,000/mm3 (whichever occurs later). Therapy may be delayed for severe 
complication. The use of growth factors should be noted if they are administered. 
 
Brentuximab vedotin: IV over 30 minutes (Do NOT give as IV push) 
Day 1 
Dose: 1.8 mg/kg/dose. (Maximum dose is 180 mg) 
 
Special precautions: Brentuximab should be administered on Day 1 prior to other 
chemotherapy. Brentuximab vedotin should be administered over approximately 30 
minutes and cannot be mixed with other medications. In-line filters should not be used 
during the IV administration. 
 
Dosing is based on patient weight according to the institutional standard. Actual weight 
will be used except for patients weighing greater than 100 kg; the dose for patients with 
weight greater than 100 kg will be calculated based on 100 kg. 
 
Dilute reconstituted product in either 0.9% Sodium Chloride Injection, USP, Lactated 
Ringer’s solution, USP, or dextrose 5% in water (D5W), USP. The final concentration of 
brentuximab vedotin in infusion bag should be in the range of 0.4–1.8 mg/mL. Refer to 
Section 6.1 for additional details. 
 
Dexamethasone: PO (may administer IV if patient unable to take oral medications) 
Days: 1-5 
Dose: 5 mg/m2/dose BID on Days 1-5. 
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. 
Liquid preparations are also acceptable. Intravenous preparation may be used temporarily 
as needed. 
 
Ifosfamide: IV over 60 minutes 
Days: 1-5 
Dose: 800 mg/m2/dose once a day. On Day 1 administer prior to methotrexate. Mesna use 
as described below. 
 
Suggested hydration: Prehydrate at 125 mL/m²/hour with a fluid containing D5W/0.45% 
NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start of ifosfamide. 
Consider adding potassium and magnesium to prevent electrolyte deficiencies. After 
completion of ifosfamide, continue hydration with fluids as recommended for 
methotrexate. Following clearance of the methotrexate, patient should receive IV or oral 
fluids at a rate of 3000 mL/m2/day until 12 hours after the last dose of ifosfamide. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
29 
 
Mesna: IV over 15 minutes (or continuous infusion as below) 
Days: 1-5 
Dose: 160 mg/m2/dose IV at hours 0 (either 15 minutes prior to or concurrently with 
ifosfamide), 4, and 8 following ifosfamide daily. 
 
When administered intravenously, the total daily mesna dose is equal to 60% of the daily 
ifosfamide dose and is administered in 3 divided doses. For example, if the dose of 
ifosfamide is 1000 mg, then the total daily mesna dose is 600 mg; 200 mg of mesna will 
be given 15 minutes before or with the ifosfamide dose (Hour 0) and 2 boluses of 200 mg 
each will be given at Hours 4 and 8. Mesna can also be administered as a continuous IV 
infusion. The continuous infusion should be started 15-30 minutes before or at the same 
time as the ifosfamide and finished no sooner than 8 hours after the end of the ifosfamide 
infusion. For example, if the dose of ifosfamide is 1000 mg, then the total daily mesna dose 
is 600 mg; the 600 mg mesna continuous infusion will start 15-30 minutes before or at the 
same time as the ifosfamide and be completed no sooner than 8 hours after the end of the 
ifosfamide infusion. If continuous infusion mesna is required, it should be given through a 
separate IV from the bicarbonate IVFs. Alternatively, mesna may be given orally as 
described below.  
 
Patients able to tolerate oral mesna may receive the second and/or the third dose(s) by 
mouth at a dosage of 40% of the ifosfamide dose. The first dose of mesna should be given 
intravenously. The oral dose of mesna is twice the IV dose and each oral dose should be 
given 2 hours earlier than an intravenous dose would be given. For example, if the dose of 
ifosfamide is 1000 mg, the first MESNA dose would be 200 mg IV at the time of the 
ifosfamide dose, followed by oral doses of 400 mg at hours 2 and 6, rather than at hours 4 
and 8. If a dose is missed, administer dose immediately. Give the next scheduled dose 
according to the original dosing schedule. Do not deviate from the original schedule. Notify 
provider if a dose is delayed or missed. If the patient vomits within 2 hours following an 
oral dose, repeat the oral dose or administer an IV dose of mesna. 
 
Methotrexate: IV over 3 hours 
Day 1 
Dose: 3000 mg/m2/dose. 
 
HD MTX Infusion Guidelines 
Methotrexate should be given on Day 1 at least 2 hours after the completion of brentuximab 
vedotin, after Day 1 ifosfamide dose, and when urine parameters are met. 
 
Hold 
trimethoprim/sulfamethoxazole 
(TMP-SMX) 
and 
any 
nonsteroidal 
anti-
inflammatory medications, penicillins, proton pump inhibitors or aspirin-containing 
medications on the day of HD MTX infusion and for at least 72 hours after the start of the 
HD MTX infusion and until the MTX level is less than 0.1 μM/L. 
 
Suggested hydration: Prehydrate with D5 ¼ NS with 30 mEq NaHCO3/L at 125 
mL/m2/hour for a minimum of 2 hours beginning after completion of brentuximab vedotin 
and until urine output is > 100 mL/m2/hour and pH is ≥ 7.0. Ringers Lactate may be used 
as the initial fluid if a bicarbonate containing solution is unavailable. Adjust fluid volume 
and sodium bicarbonate to maintain urine output and pH at above parameters. A 
bicarbonate bolus (25 mEq/m2 over 15 minutes) may be given to raise the urine pH 
relatively quickly; a normal saline bolus may also be helpful in facilitating hydration. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
30 
 
Continue hydration and alkalinization throughout MTX infusion until level is < 0.1 μM/L 
(hydrate for a minimum of 48 hours after MTX completion). Sodium bicarbonate is 
incompatible with many medications; infuse via separate line or lumen unless compatibility 
is known.  
 
Methotrexate levels: Hours 24, 48 and at least every 24 hours until level is < 0.1 μM/L: 
Draw MTX level and serum creatinine. For SCr > 125% of baseline or for MTX levels 
exceeding 50 μM/L at 24 hours or desired levels at any other time point, increase hydration 
to 200 mL/m2/hr.  
 
Leucovorin: IV or PO 
Begin 24 hours from the start of methotrexate infusion 
Dose: 15 mg/m2/dose every 6 hours until MTX level is < 0.1 µM/L. 
 
IV push or short infusion: Inject by IV push over a minimum of 3 minutes or by short 
infusion over 15 to 120 minutes. Because of the calcium content of the leucovorin solution, 
no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of 
a 10 mg/mL solution per minute). IV leucovorin and sodium bicarbonate are incompatible. 
 
Oral: Administer with or without food. Doses > 25 mg should be given IV due to the 
saturation of absorption. If the level does not fall as expected, increase the leucovorin as 
shown below: 
Schedule for calculation of leucovorin rescue based on plasma MTX levels 
MTX 
level  
µM/L 
<0.1 
0.1-2 
2-20 
20-100 
>100 
48 hrs 
None 
15 mg/m2 q6 hr 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
 100 mg/m2 q3 hr 
72 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
96 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
120 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
 
For patients who have markedly delayed MTX clearance secondary to renal dysfunction, 
consider using glucarpidase (carboxypeptidase G2). To obtain supplies of glucarpidase in 
the US contact the Voraxaze 24-hour Customer Service line at 855-786-7292. Additional 
information 
can 
be 
found 
at 
http://www.btgplc.com/products/specialty-
pharmaceuticals/voraxaze regarding product availability through ASD Healthcare, 
Cardinal, and McKesson. Canadian sites should contact McKesson at (877) 384-7425 for 
further information. Sites in Australia and New Zealand should contact Hospira at 1300-
046-774 (local) or medicalinformationAUS@hospira.com. Patients requiring glucarpidase 
rescue may remain on study, and may receive further courses of MTX at investigator 
discretion if renal function is adequate as per parameters above. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
31 
 
Cytarabine: IV over 1 – 30 minutes 
Days: 4 and 5 
Dose: 150 mg/m2/dose every 12 hours for a total of 4 doses. 
 
Etoposide: IV over 2 hours 
Days: 4 and 5 
Dose: 100 mg/m2/dose once a day  
 
Special precautions: Begin after completion of first cytarabine dose of the day. Infuse 
diluted solution (concentration ≤ 0.4 mg/mL); slow rate of administration if hypotension 
occurs. The use of an in-line filter during the infusion is suggested. Etoposide can be mixed 
in 0.9% NaCl or D5W. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
The therapy delivery maps (TDMs) for Arm BV Cycles 1, 3, and 5 are on the next page. 
Please refer to Section 7.0 for required observations. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
32 
 
4.3.1 
Course A (21 days) - Arm BV (Cycles 1, 3 & 5) 
____________________            __________________
Patient COG ID number                             DOB 
Cycle 1 should begin on Day 6 of the Prophase. Cycles 3 and 5 should begin on Day 22 following the previous cycle 
when peripheral counts have recovered with ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3. This Therapy Delivery 
Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Brentuximab vedotin 
(BREN) 
IV over 
30 minutes 
1.8 mg/kg/dose 
(Max dose 180 mg) 
Day 1 
Do NOT give as IV push 
Do not use an in-line filter. 
a. Hx; Performance Status 
b. Physical Exam (weekly in 
Cycle 1 then prior to each cycle) 
c. CBC/diff/plts (weekly) 
d. Electrolytes (weekly in 
Cycle 1 then prior to each cycle) 
e. Cr,Bilirubin,AST,ALT 
f. Urinalysis 
g. Blood for MRD (End of 
Cycle 1 only!) 
 
 
 
 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE (See Section 7.1) 
Dexamethasone 
(DEX) 
PO 
5 mg/m2/dose BID 
Days 1-5 
May give IV if unable to take 
PO. 
Ifosfamide (IFOS) 
IV over 60 
minutes 
800 mg/m2/dose once a day 
Days 1-5 
On Day 1 administer prior to 
MTX. Mesna use as described 
below. 
Mesna 
IV 
160 mg/m2/dose 
(total of 480 mg/m2/DAY) 
Days 1-5 
At hours 0, 4, and 8 following 
Ifosfamide daily. 
Methotrexate (MTX) 
IV over 
3 hours 
3000 mg/m2/dose 
Day 1 
See Section 4.3 for 
administration guidelines.  
Leucovorin (LCV) 
IV or PO* 
15 mg/m2/dose every 6 hrs 
Begin 
Day 2 
See Section 4.3 for 
administration guidelines. 24 
hrs after the START of IV 
MTX and q6 hours until the 
MTX level falls below 
0.1μM/L. * 
Cytarabine (ARAC) 
IV over 
1 – 30 minutes 
150 mg/m2/dose every 12 
hours 
Days  
4 & 5 
Give over 1 – 30 minutes every 
12 hours for total of 4 doses. 
Etoposide (ETOP) 
IV over 
2 hours 
100 mg/m2/dose once a day 
Days  
4 & 5 
Begin after completion of 1st 
Cytarabine dose each day. 
                   Enter Cycle #: _____     Ht _________cm     Wt _________kg      BSA _________m2  Growth Factor Used?: Y  /N 
 
Date 
Due 
Date 
Given 
Day 
BREN 
____mg 
DEX 
_____mg 
_____mg 
IFOS 
_____mg 
Mesna 
____mg/ 
day 
MTX 
____mg 
LCV 
____mg 
ARAC 
____mg 
ETOP 
____mg 
Studies 
Comm- 
ents 
 
 
 
Enter calculated dose above and actual dose administered below. 
 
 
1 
____mg 
____mg  
____mg 
____mg 
____mg/ 
day 
____mg 
 
 
 
a-f 
 
 
 
2 
 
____mg  
____mg 
____mg 
____mg/ 
day 
 
____* 
 
 
 
 
 
 
3 
 
____mg  
____mg 
____mg 
____mg/ 
day 
 
 
 
 
 
 
 
 
4 
 
____mg  
____mg 
____mg 
____mg/ 
day 
 
 
____mg  
____mg 
____mg 
 
 
 
 
5 
 
____mg  
____mg 
____mg 
____mg/ 
day 
 
 
____mg  
____mg 
____mg 
 
 
 
 
8 
 
 
 
 
 
 
 
 
b,c,d# 
 
 
 
15 
 
 
 
 
 
 
 
 
b,c,d# 
 
 
 
22 
Each cycle should begin on Day 22 of the previous cycle when peripheral counts have 
recovered with ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3 (whichever occurs later) 
g 
MRD is 
end of 
Cycle 1 
only 
* Please document the number of doses of Leucovorin administered. See Section 5.0 for Dose Modifications for 
Toxicities and the COG website posted materials for Supportive Care Guidelines. 
# Physical Exam and Electrolytes are weekly in cycle 1 only, then prior to each cycle. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
33 
 
4.4 
Course B (21 days) – Arm BV (Cycles 2, 4 and 6) 
 
Peripheral blood for minimal residual disease (MRD) should be drawn prior to 
beginning Cycle 2. (Time point #3) 
 
Each cycle should begin on Day 22 of the previous cycle when peripheral counts have 
recovered with ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3 (whichever occurs later). 
Therapy may be delayed for severe complication. 
 
The use of growth factors should be noted if they are administered. 
 
Brentuximab vedotin: IV over 30 minutes (Do NOT give as IV push) 
Day 1 
Dose: 1.8 mg/kg/dose. (Maximum dose is 180 mg) 
 
Special precautions: Brentuximab should be administered on Day 1 prior to other 
chemotherapy. Brentuximab vedotin should be administered over approximately 30 
minutes and cannot be mixed with other medications. In-line filters should not be used 
during the IV administration. 
 
Dosing is based on patient weight according to the institutional standard. Actual weight 
will be used except for patients weighing greater than 100 kg; the dose for patients with 
weight greater than 100 kg will be calculated based on 100 kg. 
 
Dilute reconstituted product in either 0.9% Sodium Chloride Injection, USP, Lactated 
Ringer’s solution, USP, or dextrose 5% in water (D5W), USP. The final concentration of 
brentuximab vedotin in infusion bag should be in the range of 0.4–1.8 mg/mL. 
 
Dexamethasone: PO (may administer IV if patient unable to take oral medications) 
Days 1-5 
Dose: 5 mg/m2/dose BID on Days 1-5. 
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. 
Liquid preparations are also acceptable. Intravenous preparation may be used temporarily 
as needed. 
 
Cyclophosphamide: IV over 15 - 30 minutes 
Days 1-5 
Dose: 200 mg/m2/dose. Give prior to methotrexate on Day 1.  
 
May be administered with or without further dilution. To avoid hypotonic solution, 
reconstitute Cyclophosphamide with 0.9% NaCl to a final concentration of 20 mg/mL 
 
Hydration: Patient will receive hydration for methotrexate. Following clearance of the 
methotrexate, patient should receive IV or oral fluids at a rate of 3000 mL/m2/day until 12 
hours after the last dose of cyclophosphamide. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
34 
 
Methotrexate: IV over 3 hours 
Day 1 
Dose: 3000 mg/m2/dose. 
 
HD MTX Infusion Guidelines 
Methotrexate should be given on Day 1 at least 2 hours after the completion of brentuximab 
vedotin, after Day 1 cyclophosphamide dose, and when urine parameters are met. 
 
Hold 
trimethoprim/sulfamethoxazole 
(TMP-SMX) 
and 
any 
nonsteroidal 
anti-
inflammatory medications, penicillins, proton pump inhibitors or aspirin-containing 
medications on the day of HD MTX infusion and for at least 72 hours after the start of the 
HD MTX infusion and until the MTX level is less than 0.1 μM/L. 
 
Suggested hydration: Prehydrate with D5 ¼ NS with 30 mEq NaHCO3/L at 125 
mL/m2/hour for a minimum of 2 hours beginning after completion of brentuximab vedotin 
and until urine output is > 100 mL/m2/hour and pH is ≥ 7.0. Ringers Lactate may be used 
as the initial fluid if a bicarbonate containing solution is unavailable. Adjust fluid volume 
and sodium bicarbonate to maintain urine output and pH at above parameters. A 
bicarbonate bolus (25 mEq/m2 over 15 minutes) may be given to raise the urine pH 
relatively quickly; a normal saline bolus may also be helpful in facilitating hydration. 
Continue hydration and alkalinization throughout MTX infusion until level is < 0.1 μM/L 
(hydrate for a minimum of 48 hours after MTX completion). Sodium bicarbonate is 
incompatible with many medications; infuse via separate line or lumen unless compatibility 
is known.  
 
Methotrexate levels: Hours 24, 48 and at least every 24 hours until level is < 0.1 μM/L: 
Draw MTX level and serum creatinine. 
 
For SCr > 125% of baseline or for MTX levels exceeding 50 μM/L at 24 hours or desired 
levels at any other time point, increase hydration to 200 mL/m2/hr.  
 
Leucovorin: IV or PO 
Begin 24 hours from the start of methotrexate infusion 
Dose: 15 mg/m2/dose every 6 hours until MTX level is < 0.1 µM/L. 
 
IV push or short infusion: Inject by IV push over a minimum of 3 minutes or by short 
infusion over 15 to 120 minutes. Because of the calcium content of the leucovorin solution, 
no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of 
a 10 mg/mL solution per minute). IV leucovorin and sodium bicarbonate are incompatible. 
 
Oral: Administer with or without food. Doses > 25 mg should be given IV due to the 
saturation of absorption. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
35 
 
If the level does not fall as expected, increase the leucovorin as shown below: 
 
Schedule for calculation of leucovorin rescue based on plasma MTX levels 
 
MTX 
level  
µM/L 
< 0.1 
0.1-2 
2-20 
20-100 
>100 
48 hrs 
None 
15 mg/m2 q6 hr 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
 100 mg/m2 q3 hr 
72 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
96 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
120 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
 
For patients who have markedly delayed MTX clearance secondary to renal dysfunction, 
consider using glucarpidase (carboxypeptidase G2). To obtain supplies of glucarpidase in 
the US contact the Voraxaze 24-hour Customer Service line at 855-786-7292. Additional 
information 
can 
be 
found 
at 
http://www.btgplc.com/products/specialty-
pharmaceuticals/voraxaze regarding product availability through ASD Healthcare, 
Cardinal, and McKesson. Canadian sites should contact McKesson at (877) 384-7425 for 
further information. Sites in Australia and New Zealand should contact Hospira at 1300-
046-774 (local) or medicalinformationAUS@hospira.com. Patients requiring glucarpidase 
rescue may remain on study, and may receive further courses of MTX at investigator 
discretion if renal function is adequate as per parameters above. 
 
DOXOrubicin: IV over 1-15 minutes  
Days: 4 and 5 
Dose: 25 mg/m2/dose. 
 
Administer at a concentration not to exceed 2 mg/mL by slow IV push or infusion over 
15 minutes. Infusion times may be lengthened slightly (up to 60 minutes) if institutional 
policies mandate. It is suggested that DOXOrubicin be administered through the tubing of 
rapidly infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein 
or central venous access device. 
 
Special precautions: Medication errors have occurred due to confusion between 
DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in a liposomal 
formulation. The conventional and liposomal formulations are NOT interchangeable. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery maps (TDMs) for Arm BV Cycles 2, 4, and 6 are on the next page. 
 
Please refer to Section 7.0 for required observations. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
36 
 
4.4.1 
Course B (21 days) – Arm BV (Cycles 2, 4 and 6) 
____________________      __________________ 
Patient COG ID number                       DOB 
Each cycle should begin on Day 22 following the previous cycle when peripheral counts have recovered with ANC ≥ 
500/mm3   and platelets ≥ 50,000/mm3. This Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
Brentuximab 
vedotin (BREN) 
IV over 30 
minutes 
1.8 mg/kg/dose 
(Max dose 180 mg) 
Day 1 
Do NOT give as IV Push 
Do not use an in-line filter. 
a. Physical Exam (weekly for 
Cycle 2, then prior to each cycle) 
b. Hx, Performance Status  
c. CBC/diff/plts (weekly) 
d. Electrolytes including Ca++, 
PO4, Mg++ (weekly for Cycle 2, 
then prior to each cycle) 
e. Creatinine, Bilirubin, LFTs  
f. 
CXR (PA + Lateral), CT or MRI, 
Bone Scan (for bone primary 
disease only), FDG-PET Scan 
(recommended-not mandatory)^ 
g. Urinalysis  
h. BM Aspirate/Biopsy (Bilateral) # 
i. 
Echo/EKG (prior to Cycles 4 
and 6 only) 
 
^All sites of disease should be 
evaluated after Cycle 2 and after Cycle 
4 if not in CR or CRU after Cycle 2. 
#After Cycle 2, if positive at diagnosis 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE (See Section 7.1) 
Dexamethasone 
(DEX) 
PO 
5 mg/m2/dose BID 
Days 1-5 
May give IV if unable to take 
PO. 
Cyclophosphamide 
(CPM) 
IV over 
15 - 30 
minutes 
200 mg/m2/dose 
Days 1-5 
Give prior to MTX on Day 1.  
Methotrexate 
(MTX) 
IV over 3 
hours 
3000 mg/m2/dose 
Day 1 
See Section 4.4 and for 
administration guidelines.  
Leucovorin (LCV) 
IV or PO* 
15 mg/m2/dose 
every 6 hrs 
Begin 
Day 2 
See Section 4.4 and for 
administration guidelines. 24 
hrs after the START of IV 
MTX and q6 hours until the 
MTX level falls below 
0.1μM/L. * 
DOXOrubicin 
(DOXO) 
IV over 1-15 
minutes 
25 mg/m2/dose 
Days 4 & 5 
 
 
Enter Cycle #: _____     Ht _________cm     Wt _________kg 
     BSA _________m2   Growth Factor Used?  Y/N 
 
*Please document the number of doses of Leucovorin administered. See Section 5.0 for Dose Modifications for Toxicities and the 
COG website posted materials for Supportive Care Guidelines 
$ Physical Exam and Electrolytes are weekly in Cycle 2 only, then prior to each cycle. 
^ All sites of disease should be evaluated after Cycle 2 and after Cycle 4 if not in CR or CRU after Cycle 2. 
#After Cycle 2, if positive at diagnosis. 
 
Date 
Due 
Date 
Given 
Day 
BREN 
____mg 
DEX 
_____mg _____mg 
CPM 
____mg 
MTX 
____mg 
LCV 
____mg 
DOXO 
____mg 
Studies 
Comments 
 
 
1 
____mg 
____mg  ____mg 
____mg 
____mg 
 
 
a-e, g and i 
 
 
 
2 
 
____mg  ____mg 
____mg 
 
____* 
 
 
 
 
 
3 
 
____mg  ____mg 
____mg 
 
 
 
 
 
 
 
4 
 
____mg  ____mg 
____mg 
 
 
____mg 
 
 
 
 
5 
 
____mg  ____mg 
____mg 
 
 
____mg 
 
 
 
 
8 
 
 
 
 
 
 
a,c,d$ 
 
 
 
15 
 
 
 
 
 
 
a,c,d$ 
 
 
 
22 
Each cycle should begin on Day 22 of the previous cycle when peripheral 
counts have recovered with ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3 
(whichever occurs later) 
a,c,d$,f^, h# 
 
 
 
 
For end of therapy (end of cycle 6) studies, see Section 7.1 for complete list. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
37 
 
4.5 
Course A (21 days) – Arm CZ (Cycles 1, 3 and 5) 
Prophylactic anticoagulation is required for all patients on Arm CZ starting with the 
first dose of crizotinib. See Sections 2.6 and 4.1.1 for detail. 
 
Peripheral blood for minimal residual disease (MRD) should be drawn prior to 
beginning Cycle 1. (Time point #2) 
 
Cycle 1 should begin on Day 6 of the prophase. Cycles 3 and 5 should begin on Day 22 of 
the previous cycle when peripheral counts have recovered with ANC ≥ 500/mm3 and 
platelets ≥ 50,000/mm3 (whichever occurs later). Therapy may be delayed for severe 
complication. 
 
The use of growth factors should be noted if they are administered. 
 
Crizotinib: PO BID 
Day: 1-21 
Dose: 165 mg/m2/dose (Refer to Appendix V for dosing nomogram) 
 
For patients receiving crizotinib, the capsules should not be opened and must be swallowed 
whole. If a dose is missed or forgotten at the due time, it can be taken up to (but not greater 
than) 6 hours later to help prevent missed doses. If a patient vomits after a dose, it should 
not be repeated. See Section 6.2 regarding administration instructions. Refer to the dosing 
nomogram in Appendix V for correct dose. Drug doses should be adjusted based on the 
BSA determined based on height and weight obtained within one week prior to the 
beginning of each cycle. 
 
Dexamethasone: PO (may administer IV if patient unable to take oral medications) 
Days: 1-5 
Dose: 5 mg/m2/dose BID on Days 1-5. 
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. 
Liquid preparations are also acceptable. Intravenous preparation may be used temporarily 
as needed. 
 
Ifosfamide: IV over 60 minutes 
Days: 1-5 
Dose: 800 mg/m2/dose once a day. On Day 1 administer prior to methotrexate. Mesna use 
as described below. 
 
Suggested hydration: Prehydrate at 125 mL/m²/hour with a fluid containing D5W/0.45% 
NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start of ifosfamide. 
Consider adding potassium and magnesium to prevent electrolyte deficiencies. After 
completion of ifosfamide, continue hydration with fluids as recommended for 
methotrexate. Following clearance of the methotrexate, patient should receive IV or oral 
fluids at a rate of 3000 mL/m2/day until 12 hours after the last dose of ifosfamide. 
 
Mesna: IV over 15 minutes (or continuous infusion as below) 
Days: 1-5 
Dose: 160 mg/m2/dose IV at hours 0, 4, and 8 following ifosfamide daily. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
38 
 
When administered intravenously, the total daily mesna dose is equal to 60% of the daily 
ifosfamide dose and is administered in 3 divided doses. For example, if the dose of 
ifosfamide is 1000 mg, then the total daily mesna dose is 600 mg; 200 mg of mesna will 
be given 15 minutes before or with the ifosfamide dose (Hour 0) and 2 boluses of 200 mg 
each will be given at Hours 4 and 8. Mesna can also be administered as a continuous IV 
infusion. The continuous infusion should be started 15-30 minutes before or at the same 
time as the ifosfamide and finished no sooner than 8 hours after the end of the ifosfamide 
infusion. For example, if the dose of ifosfamide is 1000 mg, then the total daily mesna dose 
is 600 mg; the 600 mg mesna continuous infusion will start 15-30 minutes before or at the 
same time as the ifosfamide/cyclophosphamide and be completed no sooner than 8 hours 
after the end of the ifosfamide infusion. If continuous infusion mesna is required, it should 
be given through a separate IV from the bicarbonate IVFs. Alternatively, mesna may be 
given orally as described below.  
 
Patients able to tolerate oral mesna may receive the second and/or the third dose(s) by 
mouth at a dosage of 40% of the ifosfamide dose. The first dose of mesna should be given 
intravenously. The oral dose of mesna is twice the IV dose and each oral dose should be 
given 2 hours earlier than an intravenous dose would be given. For example, if the dose of 
ifosfamide is 1000 mg, the first MESNA dose would be 200 mg IV at the time of the 
ifosfamide dose, followed by oral doses of 400 mg at hours 2 and 6, rather than at hours 4 
and 8. If a dose is missed, administer dose immediately. Give the next scheduled dose 
according to the original dosing schedule. Do not deviate from the original schedule. Notify 
provider if a dose is delayed or missed. If the patient vomits within 2 hours following an 
oral dose, repeat the oral dose or administer an IV dose of mesna. 
 
Methotrexate: IV over 3 hours 
Day 1 
Dose: 3000 mg/m2/dose. 
 
HD MTX Infusion Guidelines 
Methotrexate should be given on Day 1 after Day 1 ifosfamide dose and when urine 
parameters are met. 
 
Hold 
trimethoprim/sulfamethoxazole 
(TMP-SMX) 
and 
any 
nonsteroidal 
anti-
inflammatory medications, penicillins, proton pump inhibitors or aspirin-containing 
medications on the day of HD MTX infusion and for at least 72 hours after the start of the 
HD MTX infusion and until the MTX level is less than 0.1 μM/L. 
 
Suggested hydration: Prehydrate with D5 ¼ NS with 30 mEq NaHCO3/L at 
125 mL/m2/hour for a minimum of 2 hours and until urine output is > 100 mL/m2/hour and 
pH is ≥ 7.0. Ringers Lactate may be used as the initial fluid if a bicarbonate containing 
solution is unavailable. Adjust fluid volume and sodium bicarbonate to maintain urine 
output and pH at above parameters. A bicarbonate bolus (25 mEq/m2 over 15 minutes) may 
be given to raise the urine pH relatively quickly; a normal saline bolus may also be helpful 
in facilitating hydration. Continue hydration and alkalinization throughout MTX infusion 
until level is < 0.1 μM/L (hydrate for a minimum of 48 hours after MTX completion). 
Sodium bicarbonate is incompatible with many medications; infuse via separate line or 
lumen unless compatibility is known.  
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
39 
 
Methotrexate levels: Hours 24, 48 and at least every 24 hours until level is < 0.1 μM/L: 
Draw MTX level and serum creatinine. For SCr > 125% of baseline or for MTX levels 
exceeding 50 μM/L at 24 hours or desired levels at any other time point, increase hydration 
to 200 mL/m2/hr.  
 
Leucovorin: IV or PO 
Begin 24 hours from the start of methotrexate infusion 
Dose: 15 mg/m2/dose every 6 hours until MTX level is < 0.1 µM/L. 
 
IV push or short infusion: Inject by IV push over a minimum of 3 minutes or by short 
infusion over 15 to 120 minutes. Because of the calcium content of the leucovorin solution, 
no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of 
a 10 mg/mL solution per minute). IV leucovorin and sodium bicarbonate are incompatible. 
 
Oral: Administer with or without food. Doses > 25 mg should be given IV due to the 
saturation of absorption. 
 
If the level does not fall as expected, increase the leucovorin as shown below: 
 
Schedule for calculation of leucovorin rescue based on plasma MTX levels 
MTX level µM/L 
< 0.1 
0.1-2 
2-20 
20-100 
> 100 
48 hrs 
None 
15 mg/m2 q6 hr 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
 100 mg/m2 q3 hr 
72 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
96 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
120 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
For patients who have markedly delayed MTX clearance secondary to renal dysfunction, 
consider using glucarpidase (carboxypeptidase G2). To obtain supplies of glucarpidase in 
the US contact the Voraxaze 24-hour Customer Service line at 855-786-7292. Additional 
information 
can 
be 
found 
at 
http://www.btgplc.com/products/specialty-
pharmaceuticals/voraxaze regarding product availability through ASD Healthcare, 
Cardinal, and McKesson. Canadian sites should contact McKesson at (877) 384-7425 for 
further information. Sites in Australia and New Zealand should contact Hospira at 1300-
046-774 (local) or medicalinformationAUS@hospira.com. Patients requiring glucarpidase 
rescue may remain on study, and may receive further courses of MTX at investigator 
discretion if renal function is adequate as per parameters above. 
 
Cytarabine: IV over 1 – 30 minutes  
Days: 4 and 5 
Dose: 150 mg/m2/dose every 12 hours for a total of 4 doses. 
 
Etoposide: IV over 2 hours 
Days: 4 and 5 
Dose: 100 mg/m2/dose once a day 
 
Special precautions: Begin after completion of first cytarabine dose of the day. Infuse 
diluted solution (concentration ≤ 0.4 mg/mL); slow rate of administration if hypotension 
occurs. The use of an in-line filter during the infusion is suggested. Etoposide can be mixed 
in 0.9% NaCl or D5W. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
The therapy delivery maps (TDMs) for Arm CZ Cycles 1, 3, and 5 are on the next page. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
40 
 
4.5.1 
Course A (21 days) – Arm CZ (Cycles 1, 3 and 5) 
____________________         __________________ 
Patient COG ID number                       DOB 
Cycle 1 should begin on Day 6 of the prophase. Cycles 3 and 5 should begin on Day 22 following the previous cycle when peripheral counts have 
recovered with ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3. This Therapy Delivery Map is on one (1) page. 
Enter Cycle #: _____     Ht _________cm     Wt _________kg 
     BSA _________m2     Growth Factor Used?:  Y  /  N 
 
Date 
Due 
Date 
Given 
Day 
CRIZ 
___mg ___mg 
DEX 
___mg 
___mg 
IFOS 
___mg 
Mesna 
___mg/ day 
MTX 
___mg 
LCV 
__mg 
ARAC 
___mg 
___mg 
ETOP 
___mg 
Studies 
Comment 
 
 
 
Enter calculated dose above and actual dose administered below. 
 
 
1 
___mg ___mg 
___mg 
___mg 
____mg 
____mg/day 
____mg 
 
 
 
a-f  
 
 
 
2 
___mg ___mg 
___mg 
___mg 
____mg 
____mg/day 
 
___* 
 
 
 
 
 
 
3 
___mg ___mg 
___mg 
___mg 
____mg 
____mg/day 
 
 
 
 
 
 
 
 
4 
___mg ___mg 
___mg 
___mg 
____mg 
____mg/day 
 
 
___mg 
___mg 
___mg 
 
 
 
 
5 
___mg ___mg 
___mg 
___mg 
____mg 
____mg/day 
 
 
___mg 
___mg 
___mg 
 
 
 
 
6 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
7 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
8 
___mg ___mg 
 
 
 
 
 
 
 
a,b,c,d# 
 
 
 
9 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
10 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
11 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
12 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
13 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
14 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
15 
___mg ___mg 
 
 
 
 
 
 
 
a,b,c,d# 
 
 
 
16 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
17 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
18 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
19 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
20 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
21 
___mg ___mg 
 
 
 
 
 
 
 
 
 
 
 
22 
Begin next cycle on Day 22 of the previous cycle when peripheral counts have recovered with 
ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3 (whichever occurs later). 
a,b, c,d#,g 
 
* Please document the number of doses of Leucovorin administered. See Section 5.0 for Dose Modifications for Toxicities and the COG website posted 
materials for Supportive Care Guidelines.  # Physical Exam and Electrolytes are weekly in Cycle 1 only, then prior to each cycle. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Crizotinib 
(CRIZ) 
PO 
165 mg/m2/dose BID 
Days 1-21 
See Appendix V for dosing.  
See Section 4.1.1 for required 
prophylactic anticoagulation. 
a. Hx; Performance Status 
b. Physical Exam (weekly in cycle 1 
then prior to each cycle) 
c. CBC/diff/plts (weekly) 
d. Electrolytes (weekly in cycle 1 then 
prior to each cycle) 
e. Cr, Bilirubin, AST, ALT 
f. Urinalysis 
g. Blood for MRD (End of Cycle 1 
only!) 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE  (See Section 7.1) 
Dexamethasone 
(DEX) 
PO 
5 mg/m2/dose BID 
Days 1-5 
May give IV if unable to take PO. 
Ifosfamide 
(IFOS) 
IV over 
60 minutes 
800 mg/m2/dose once a 
day 
Days 1-5 
On Day 1 administer prior to MTX. 
Mesna use as described below. 
Mesna 
IV 
160 mg/m2/dose 
Days 1-5 
At hours 0, 4, and 8 following 
Ifosfamide daily. 
Methotrexate 
(MTX) 
IV over 3 hours 
3000 mg/m2/dose 
Day 1 
See Section 4.5 for administration 
guidelines. 
Leucovorin 
(LCV) 
IV or PO* 
15 mg/m2/dose every 6 
hrs 
Begin 
Day 2 
See Section 4.5 for administration 
guidelines. 24 hrs after the START of 
IV MTX and q6 hours until the MTX 
level falls below 0.1μM/L. * 
Cytarabine 
(ARAC) 
IV over 
1 – 30 minutes 
150 mg/m2/dose every 12 
hours 
Days   
4 & 5 
Give over 1 – 30 minutes every 
12 hours for total of 4 doses. 
Etoposide 
(ETOP) 
IV over 2 hours 
100 mg/m2/dose once a 
day 
Days  
4 & 5 
Begin after completion of 1st 
Cytarabine dose each day. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
41 
 
4.6 
Course B (21 days) – Arm CZ (Cycles 2, 4 and 6) 
 
Prophylactic anticoagulation is required for all patients on Arm CZ starting with the 
first dose of crizotinib. See Sections 2.6 and 4.1.1 for detail. 
 
Peripheral blood for MDD/MRD should be drawn prior to beginning Cycle 2. (Time 
point #3) 
 
Each cycle should begin on Day 22 of the previous cycle when peripheral counts have 
recovered with ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3 (whichever occurs later). 
Therapy may be delayed for severe complication. 
 
The use of growth factors should be noted if they are administered. 
 
Crizotinib: PO BID 
Day: 1-21 
Dose: 165 mg/m2/dose (Refer to Appendix V for dosing nomogram.) 
 
For patients receiving crizotinib, the capsules should not be opened and must be swallowed 
whole. If a dose is missed or forgotten at the due time, it can be taken up to (but not greater 
than) 6 hours later to help prevent missed doses. If a patient vomits after a dose, it should 
not be repeated. See Section 6.2 regarding administration instructions. Refer to the dosing 
nomogram in Appendix V for correct dose group. Drug doses should be adjusted based on 
the BSA determined based on height and weight obtained within one week prior to the 
beginning of each cycle. 
 
Dexamethasone: PO (may administer IV if patient unable to take oral medications) 
Days 1-5 
Dose: 5 mg/m2/dose BID on Days 1-5. 
 
Each dose may be adjusted upward to the nearest 0.25 mg as necessary for tablet size. 
Liquid preparations are also acceptable. Intravenous preparation may be used temporarily 
as needed. 
 
Cyclophosphamide: IV over 15 - 30 minutes 
Days 1-5 
Dose: 200 mg/m2/dose. Give prior to methotrexate on Day 1.  
 
May be administered with or without further dilution. To avoid hypotonic solution, 
reconstitute Cyclophosphamide with 0.9% NaCl to a final concentration of 20 mg/mL  
 
Hydration: Patient will receive hydration for methotrexate. Following clearance of the 
methotrexate, patient should receive IV or oral fluids at a rate of 3000 mL/m2/day until 12 
hours after the last dose of cyclophosphamide. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
42 
 
Methotrexate: IV over 3 hours 
Day 1 
Dose: 3000 mg/m2/dose. 
 
HD MTX Infusion Guidelines 
Methotrexate should be given on Day 1 after Day 1 cyclophosphamide dose and when 
urine parameters are met. 
 
Hold 
trimethoprim/sulfamethoxazole 
(TMP-SMX) 
and 
any 
nonsteroidal 
anti-
inflammatory medications, penicillins, proton pump inhibitors or aspirin-containing 
medications on the day of HD MTX infusion and for at least 72 hours after the start of the 
HD MTX infusion and until the MTX level is less than 0.1 μM/L. 
 
Suggested hydration: Prehydrate with D5 ¼ NS with 30 mEq NaHCO3/L at 
125 mL/m2/hour for a minimum of 2 hours and until urine output is > 100 mL/m2/hour and 
pH is ≥ 7.0. Ringers Lactate may be used as the initial fluid if a bicarbonate containing 
solution is unavailable. Adjust fluid volume and sodium bicarbonate to maintain urine 
output and pH at above parameters. A bicarbonate bolus (25 mEq/m2 over 15 minutes) may 
be given to raise the urine pH relatively quickly; a normal saline bolus may also be helpful 
in facilitating hydration. Continue hydration and alkalinization throughout MTX infusion 
until level is < 0.1 μM/L (hydrate for a minimum of 48 hours after MTX completion). 
Sodium bicarbonate is incompatible with many medications; infuse via separate line or 
lumen unless compatibility is known.  
 
Methotrexate levels: Hours 24, 48 and at least every 24 hours until level is < 0.1 μM/L: 
Draw MTX level and serum creatinine. 
 
For SCr > 125% of baseline or for MTX levels exceeding 50 μM/L at 24 hours or desired 
levels at any other time point, increase hydration to 200 mL/m2/hr. 
 
Leucovorin: IV or PO 
Begin 24 hours from the start of methotrexate infusion 
Dose: 15 mg/m2/dose every 6 hours until MTX level is < 0.1 µM/L. 
 
IV push or short infusion: Inject by IV push over a minimum of 3 minutes or by short 
infusion over 15 to 120 minutes. Because of the calcium content of the leucovorin solution, 
no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of 
a 10 mg/mL solution per minute). IV leucovorin and sodium bicarbonate are incompatible. 
 
Oral: Administer with or without food. Doses > 25 mg should be given IV due to the 
saturation of absorption. 
 
If the level does not fall as expected, increase the leucovorin as shown below: 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
43 
 
 
Schedule for calculation of leucovorin rescue based on plasma MTX levels 
 
MTX level  
µM/L 
< 0.1 
0.1-2 
2-20 
20-100 
> 100 
48 hrs 
None 
15 mg/m2 q6 hr 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
 100 mg/m2 q3 hr 
72 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
96 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
120 hrs 
None 
15 mg/m2 q6 hr 
10 mg/m2 q3 hr 
100 mg/m2 q3 hr 
1000 mg/m2 q3 hr* 
 
For patients who have markedly delayed MTX clearance secondary to renal dysfunction, 
consider using glucarpidase (carboxypeptidase G2). To obtain supplies of glucarpidase in 
the US contact the Voraxaze 24-hour Customer Service line at 855-786-7292. Additional 
information 
can 
be 
found 
at 
http://www.btgplc.com/products/specialty-
pharmaceuticals/voraxaze regarding product availability through ASD Healthcare, 
Cardinal, and McKesson. Canadian sites should contact McKesson at (877) 384-7425 for 
further information. Sites in Australia and New Zealand should contact Hospira at 1300-
046-774 (local) or medicalinformationAUS@hospira.com. Patients requiring glucarpidase 
rescue may remain on study, and may receive further courses of MTX at investigator 
discretion if renal function is adequate as per parameters above. 
 
DOXOrubicin: IV over 1-15 minutes  
Days: 4 and 5 
Dose: 25 mg/m2/dose. 
 
Administer at a concentration not to exceed 2 mg/mL by slow IV push or infusion over 
15 minutes. Infusion times may be lengthened slightly (up to 60 minutes) if institutional 
policies mandate. It is suggested that DOXOrubicin be administered through the tubing of 
rapidly infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein or 
central venous access device. 
 
Special precautions: Medication errors have occurred due to confusion between 
DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in a liposomal formulation. 
The conventional and liposomal formulations are NOT interchangeable. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery maps (TDMs) for Arm CZ Cycles 2, 4, and 6 are on the next page. 
 
Please refer to Section 7.0 for required observations. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
44 
 
4.6.1 
Course B (21 days) – Arm CZ (Cycles 2, 4 & 6) 
____________________            __________________ 
Patient COG ID number                            DOB 
Each cycle should begin on Day 22 following the previous cycle when peripheral counts have recovered with ANC ≥ 500/mm3 
and platelets ≥ 50,000/mm3. This Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
NOTES 
OBSERVATIONS 
Crizotinib (CRIZ) 
PO 
165 mg/m2/dose BID 
Days 1-21 
See Appendix V for dosing. 
See Section 4.1.1 for required 
prophylactic anticoagulation. 
a. Physical Exam (weekly for Cycle 2, then 
prior to each cycle) 
b. Hx, Performance Status (prior to each cycle) 
c. CBC/diff/plts (weekly) 
d. Electrolytes including Ca++, PO4, Mg++ 
(weekly for Cycle 2, then prior to each 
cycle) 
e. Creatinine, Bilirubin, LFTs (prior to each 
cycle) 
f. CXR(PA + Lateral), CT or MRI, Bone Scan 
(for bone primary disease only), FDG-PET 
Scan (recommended-not mandatory)^ 
g. Urinalysis (prior to each cycle) 
h. BM Aspirate/Biopsy (Bilateral) # 
i. Echo/EKG (prior to Cycles 4 and 6 only) 
 
^All sites of disease should be evaluated after 
Cycle 2 and after Cycle 4 if not in CR or CRU 
after Cycle 2. 
#After Cycle 2, if positive at diagnosis 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT CARE  
(See Section 7.1) 
Dexamethasone 
(DEX) 
PO  
5 mg/m2/dose BID 
Days 1-5 
May give IV if unable to take 
PO. 
Cyclophosphamide 
(CPM) 
IV over 
15 - 30 
minutes 
200 mg/m2/dose 
Days 1-5 
Give prior to MTX on Day 1.  
Methotrexate 
(MTX) 
IV over 3 
hours 
3000 mg/m2/dose 
Day 1 
See Section 4.6  for 
administration guidelines. 
Leucovorin (LCV) 
IV or PO* 
15 mg/m2/dose every 
6 hrs 
Day 2 
See Section 4.6 for 
administration guidelines. 24 
hrs after the START of IV 
MTX and q6 hours until the 
MTX level falls below 
0.1μM/L. 
DOXOrubicin 
(DOXO) 
IV over 1-
15 minutes 
25 mg/m2/dose 
Days 
4 & 5 
 
Enter Cycle #: _____     Ht _________cm     Wt _________kg 
     BSA _________m2     Growth Factor Used?  Y  /  N
* Please document the number of doses of Leucovorin administered. See Section 5.0 for Dose Modifications for Toxicities and the 
COG website posted materials for Supportive Care Guidelines. 
$ Physical Exam and Electrolytes are weekly in Cycle 1 only, then prior to each cycle. 
^ All sites of disease should be evaluated after Cycle 2 and after Cycle 4 if not in CR or CRU after Cycle 2. 
# After Cycle 2, if positive at diagnosis. 
 
Date 
Due 
Date 
Given 
Day 
CRIZ 
___mg  ___mg 
DEX 
___mg  ___mg 
CPM 
____mg 
MTX 
____mg 
LCV 
____mg 
DOXO 
____mg 
Studies 
Comment 
Enter calculated dose above and actual dose administered below. 
 
 
1 
___mg  ___mg 
___mg  ___mg 
____mg 
____mg 
 
 
a-e, g and i 
 
 
 
2 
___mg  ___mg 
___mg  ___mg 
____mg 
 
____* 
 
 
 
 
 
3 
___mg  ___mg 
___mg  ___mg 
____mg 
 
 
 
 
 
 
 
4 
___mg  ___mg 
___mg  ___mg 
____mg 
 
 
____mg 
 
 
 
 
5 
___mg  ___mg 
___mg  ___mg 
____mg 
 
 
____mg 
 
 
 
 
6 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
7 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
8 
___mg  ___mg 
 
 
 
 
 
a,c,d$ 
 
 
 
9 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
10 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
11 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
12 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
13 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
14 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
15 
___mg  ___mg 
 
 
 
 
 
a,c,d$ 
 
 
 
16 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
17 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
18 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
19 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
20 
___mg  ___mg 
 
 
 
 
 
 
 
 
 
21 
___mg  ___mg 
 
 
 
 
 
a,c,d$, f^,h# 
 
 
 
22 
 
Each cycle should begin on Day 22 of the previous cycle when peripheral counts have 
recovered with ANC ≥ 500/mm3 and platelets ≥ 50,000/mm3 (whichever occurs later) 
 
 
 
 
 
For end of therapy (end of Cycle 6) studies, see Section 7.1 for complete list. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
45 
 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
The Study Chair must be notified of any dosage modification. The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized for grading and reporting adverse events. 
 
5.1 
Brentuximab vedotin (SGN-35) 
 
5.1.1 
Suggested Dose Modifications/Delays guidelines 
 
Intrapatient Dose Reductions for Starting Dose of 1.8 mg/kg Every 3 Weeks 
Treatment Modification Guidelines for SGN-35 Related Adverse Events 
 
Dose Level 
Dose 
Starting Dose 
1.8mg/kg (max dose 180 mg) 
Dose Reduction #1 
1.2 mg/kg (max dose 120 mg) 
Dose Reduction #2 
0.8 mg/kg (max dose 80 mg) 
 
Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
Allergic reactions,  
or  
Acute infusional 
reactions/ cytokine 
release syndrome 
Grade 1-2 
 
For first reaction: 
• 
Hold the infusion and wait 30 to 60 minutes (depending upon the 
reaction severity). 
• 
Treat reactions with diphenhydramine 1 mg/kg (max 50 mg), or 
follow local institution guidelines. Depending on the reaction 
severity, dexamethasone 0.2 mg/kg (max 10 mg) IV should be used. 
• 
Upon resolution of the symptoms, at the physician’s discretion, it may 
be possible to resume treatment by administering an H2 blocker 
approximately 
30 minutes 
before 
restarting 
the 
infusion. 
Acetaminophen can also be considered. Dosing of SGN-35 should be 
administered at half of the previously administered rate. 
For subsequent doses:  
 
• 
Utilize diphenhydramine with or without acetaminophen as pre-
treatment for all subsequent infusions.   
• 
Dosing should be administered over the shortest period that was well 
tolerated. 
If Grade 1-2 infusion reactions recur despite the above measures, either 
during re-challenge or subsequent treatments: 
• 
Take the measures outlined above. 
• 
With subsequent dosing, add dexamethasone 0.2 mg/kg (max 10 mg) 
IV or equivalent to medications above prior to infusion. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
46 
 
Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
Grade 3 
• 
Stop infusion immediately. 
• 
Administer diphenhydramine hydrochloride 1 mg/kg IV (max 50 mg), 
dexamethasone 0.2 mg/kg (max 10 mg) IV (or equivalent), 
bronchodilators for bronchospasms, and other medications as 
medically indicated. 
• 
Once symptoms recover, brentuximab vedotin should not be resumed 
for that course. 
• 
Subsequent courses of brentuximab vedotin may be considered at 
physicians’ discretion, after a discussion and approval by CTEP.  
• 
All subsequent infusions should use the following premedications 
prior to infusion, diphenhydramine hydrochloride 1 mg/kg IV (max 
50 mg), dexamethasone 0.2 mg/kg (max 10 mg) IV (or equivalent). In 
addition, the infusion should be administered at 50% of the previous 
infusion rate. 
Grade 4 
• 
Stop infusion immediately. 
• 
Administer diphenhydramine hydrochloride 1 mg/kg (max 50 mg) IV, 
dexamethasone 0.2 mg/kg (max 10 mg) IV (or equivalent), and other 
anaphylaxis medications as indicated. 
• 
Epinephrine or bronchodilators should be administered as indicated. 
• 
Hospital admission for observation may be indicated. 
• 
Discontinue SGN-35. 
Anaphylaxis 
Any Grade 
• 
If anaphylaxis occurs, immediately and permanently discontinue 
administration of SGN-35 and administer appropriate medical therapy. 
Pancreatitis 
Grade 2 
• 
Withhold dose until toxicity has returned to baseline, then continue on 
protocol therapy but should resume at one dose reduction. 
• 
If Grade 2 pancreatitis recurs after one dose reduction, the patient must 
be removed from protocol therapy. 
Grade 3-4 
• 
Permanently discontinue brentuximab vedotin. 
Peripheral Neuropathy 
Grade 1 
• 
Continue at same dose level. 
Grade 2 
• 
Reduce dose by one level and continue treatment. If already dose 
reduced previously then continue dosing at that level. 
Grade 3 
• 
Treatment should be delayed up to 1 week after all other parameters to 
proceed are met to see if neuropathy improves to ≤ Grade 2. If 
neuropathy returns to ≤ Grade 2 then proceed with next treatment 
reduced by one dose level. If neuropathy remains Grade 3 then SGN-
35 should be held and then reduced by one dose level for subsequent 
treatments assuming neuropathy has returned to ≤ Grade 2. 
• 
Patients who develop Grade 3 neuropathy after dose reduction of 
SGN-35 will have SGN-35 discontinued 
Grade 4 
• 
Discontinue SGN-35. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
47 
 
Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
Pneumonitis 
Grade 1 
• 
Continue at same dose level. 
Grade 2 
• 
If suspected, strongly consider administration of 100 mg of oral or 
intravenous prednisolone in single daily or two divided doses. The 
suggested dose for patients who develop pulmonary toxicity is 
methylprednisolone 1 mg/kg IV every 12 hours for a minimum of 
seven days. 
• 
Upon occurrence of pneumonitis, study therapy should be held, and 
the Study Chair and Research Coordinator should be notified within 
48 hours. 
• 
CTEP must be notified within 7 days of study chair notification of each 
instance of Grade 2 pneumonitis. The Study Chair and CTEP will 
review the history of the affected patient and the pulmonary toxicity 
for the trial as a whole before proceeding with the recommendation to 
resume protocol therapy at a lower dose level. Failure to discuss a case 
of pulmonary toxicity will lead to suspension of accrual. 
Grade 3-4 
• 
If suspected, strongly consider administration of 100 mg of oral or 
intravenous prednisolone in single daily or two divided doses. The 
suggested dose for patients who develop pulmonary toxicity is 
methylprednisolone 1 mg/kg IV every 12 hours for a minimum of 
seven days. 
• 
Discontinue brentuximab vedotin. 
• 
The Study Chair and Research Coordinator should be notified within 
48 hours. 
• 
CTEP must be notified within 7 days of the notification of the 
Study Chair. 
Progressive Multifocal 
Leukoencephalopathy 
(PML) 
Any Grade 
If PML is suspected, a diagnostic work-up should be performed. The work-
up may include, but is not limited to the following: 
• 
Neurologic examinations and neurology consultation, as warranted. 
• 
Brain MRI. Features suggestive of PML include presence of unifocal 
or multifocal lesions, mainly of the white matter, which are typically 
non-enhancing and do not have mass effect. 
• 
PCR analysis. JCV DNA, detectable in CSF or in a brain biopsy, is 
suggestive of PML. 
Brentuximab vedotin dosing should be held if PML is suspected.  
If PML is confirmed, brentuximab vedotin should be permanently 
discontinued. 
Lymphopenia 
Grade 1-4 
• 
Continue at same dose level. 
Neutropenia 
Grade 1-2 
• 
Continue at same dose level. 
Grade 3-4 
• 
Neutropenia is to be expected on this protocol. Patients who are unable 
to start a cycle > 35 days after the start of the previous cycle (>14 day 
delay) due to neutropenia with no other dose-limiting toxicity should 
receive the same dose in the next cycle with myeloid growth factor 
support. 
• 
Patients who are unable to start a cycle > 35 days after the start of the 
previous cycle (>14 day delay) with myeloid growth factor support 
due to neutropenia with no other dose-limiting toxicity should have 
SGN-35 reduced by 1 dose level. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
48 
 
Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
Thrombocytopenia 
Grade 1-2 
• 
Continue at same dose level. 
Grade 3-4 
• 
Thrombocytopenia is expected on this protocol. Continue at current 
dose level. 
Non-hematologic events 
(except electrolyte 
abnormalities and those 
noted elsewhere in table) 
that are probably or 
definitely related  
Grade 1-2 
• 
Continue at same dose level. 
Grade 3-4 
• 
Withhold dose until toxicity is ≤ Grade 2 or has returned to baseline, 
then continue on protocol therapy but should resume at one dose 
reduction. 
• 
If same non-hematological Grade 3-4 toxicity recurs after one dose 
reduction, SGN-35 should be omitted. 
Electrolyte Abnormalities 
Grade 1-4 
• 
Continue at same dose level, provided electrolyte toxicity is not 
medically consequential and has been readily corrected. 
• 
If electrolyte abnormality is medically consequential, refer to 
guidelines above for non-hematologic events. 
Renal Impairment  
 
• 
Omit for patients with severe renal impairment (CLcr  < 30mL/min) 
Mucositis 
Grade 1-3 
• 
Continues at same dose level 
Grade 4 
• 
Withold drug until toxicity is ≤ Grade 2, then resume treatment 
reduced by one dose level 
 
5.2 
Crizotinib 
 
5.2.1 
Hematological Toxicity 
Patients who are unable to start a cycle > 35 days after the start of the previous 
cycle (> 14 day delay) due to neutropenia with no other dose-limiting toxicity 
should receive the same dose in the next cycle with myeloid growth factor support. 
 
Patients who are unable to start a cycle > 35 days after the start of the previous 
cycle ( > 14 day delay) with myeloid growth factor support due to neutropenia with 
no other dose-limiting toxicity should have crizotinib reduced by 1 dose level. 
 
5.2.2 
Therapy Delay  
Crizotinib should only be given for 21 days each cycle. If the next cycle is delayed 
due to other reasons, crizotinib should not be given until the next cycle is started. 
 
5.2.3 
Hepatic Toxicity  
Patients are expected to have temporary increases in liver enzymes secondary to 
other chemotherapeutic agents. 
 
Patients with Grade 3-4 liver enzyme elevation, including ALT/AST/GGT, will 
have crizotinib held until levels recover to ≤ Grade 1 (< 2.5 X ULN) or baseline. 
See below table for adjustments. 
 
5.2.4 
Renal Cyst  
The development of complex renal cysts has been reported in some patients with 
NSCLC treated with crizotinib. These cysts may be symptomatic or asymptomatic, 
and have usually developed within the first several months of starting crizotinib. 
The precise nature and significance of these cysts is unclear; however, while no 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
49 
 
evidence of malignancy has been found based on aspiration of cyst fluid and biopsy 
in the reported cases, complex renal cysts may be associated with renal 
malignancy, and thus consultation with an urologist or suitable alternate medical 
expert is recommended. Monitoring of complex renal cysts with appropriate 
imaging should be performed as scheduled per protocol with contrast-enhanced 
CT scanning or magnetic resonance imagining assuring full visualization of the 
kidneys. 
Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
Hepatic toxicity: 
Increased ALT  
Grades 3 – 4 
Patients with Grade 3-4 liver enzyme elevation, including 
ALT/AST/GGT, will have crizotinib held until levels recover to ≤ Grade 1 
(< 2.5 X ULN) or baseline. 
• 
If levels recover within 7 days of study drug interruption, this is not 
considered dose limiting and crizotinib will be continued at the same 
dose. 
• 
If levels recover > 7 days after interruption of study drug but < 21 
days from the planned start of the next cycle, the patient may 
continue on protocol therapy but should receive subsequent doses of 
crizotinib at the next lower dose level (see Appendix V and reduce 
by one dose group). 
• 
If levels do not meet criteria within 21 days after the planned start of 
the next treatment cycle, this is a DLT and the patient should not 
receive any further crizotinib. 
Left ventricular systolic 
dysfunction 
Grades 1 – 2 
• 
Continue at the same dose level. 
Grades 3 – 4 
• 
Discontinue treatment and do not retreat. 
Pneumonitis  
(in absence of disease 
progression in the lung, 
infection, other 
pulmonary disease, or 
radiation effect) 
Grade 1 
• 
Continue at the same dose level. 
Grade 2 
• 
If suspected, strongly consider administration of 100 mg of oral or 
intravenous prednisolone in single daily or two divided doses.  The 
suggested dose for patients who develop pulmonary toxicity is 
methylprednisolone 1 mg/kg IV every 12 hours for a minimum of 
seven days. 
• 
Upon occurrence of pneumonitis, study therapy should be held, and 
the Study Chair and Research Coordinator should be notified within 
48 hours. 
• 
CTEP must be notified within 7 days of study chair notification 
of each instance of Grade 2 pneumonitis. The Study Chair and 
CTEP will review the history of the affected patient and the 
pulmonary toxicity for the trial as a whole before proceeding 
with the recommendation to resume protocol therapy at a lower 
dose level. Failure to discuss a case of pulmonary toxicity will 
lead to suspension of accrual. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
50 
 
Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
Grades 3 – 4 
• 
If suspected, strongly consider administration of 100 mg of oral or 
intravenous prednisolone in single daily or two divided doses.  The 
suggested dose for patients who develop pulmonary toxicity is 
methylprednisolone 1 mg/kg IV every 12 hours for a minimum of 
seven days. 
• 
Discontinue crizotinib and do not retreat. 
• 
The Study Chair and Research Coordinator should be notified within 
48 hours. 
• 
CTEP must be notified within 7 days of the notification of the 
Study Chair. 
Prolonged QTc interval 
(as confirmed by a 
cardiologist at the site) 
Grade 1 
• 
Continue at the same dose level. 
Grade 2 
• 
Continue at the same dose level. Assess electrolytes (particularly 
Ca++, K+, Mg+) and concomitant medications 
• 
Correct any electrolyte abnormalities. 
Grade 3 
• 
Withhold current dose until recovery to Grade 1. Assess and correct 
electrolytes (particularly Ca++, K+, Mg+) and concomitant 
medications. Upon recovery to Grade 1, resume treatment by 
reducing the dose by 1 dose level if no other cause for QTc 
prolongation is found, otherwise resume at the same dose. 
Grade 4 
• 
Discontinue treatment and do not retreat. 
Thromboembolic 
Events 
Grade 1 
• 
Continue at same dose level. 
Grades 2-3 
• 
Crizotinib should be held at least 1 week and up to 2 weeks. If the 
thrombosis is considered controlled on anticoagulation and the 
patient is able to proceed with chemotherapy then proceed with 
treatment reduced by one dose level. If after 2 weeks patient still has 
clinical symptoms from the event, then crizotinib should be 
discontinued permanently. 
• 
Patients who develop a subsequent Grade 2-4 event after dose 
reduction will have crizotinib discontinued permanently. 
Grade 4 
• 
Discontinue crizotinib treatment permanently. 
Non-hematologic events 
(except electrolyte 
abnormalities and 
those noted elsewhere 
in table) that are 
probably or definitely 
related 
Grades 1 – 2 
• 
Continue at same dose level. 
Grades 3 – 4 
• 
Withhold dose until toxicity is ≤ Grade 2 or has returned to baseline, 
then continue on protocol therapy but should receive subsequent 
doses of crizotinib at the next lower dose level (see Appendix V and 
reduce by one dose group). 
• 
If same non-hematological Grade 3-4 toxicity recurs after one dose 
reduction (as stated above), crizotinib should be omitted. 
Visual Disturbance 
Grades 1-2 
• 
Continue at the same dose level. Repeat Ophthalmologic 
examination. 
Grade 3 
• 
Interrupt crizotinib until recovery. Repeat ophthalmologic 
examination+. Resume treatment by reducing by one dose level. 
Grade 4 
• 
Discontinue treatment and do not retreat. Repeat ophthalmologic 
examination+. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
51 
 
Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
Mucositis 
Grade 1-3 
• 
Continues at same dose level 
Grade 4 
• 
Withold drug until toxicity is ≤ Grade 2, then resume treatment 
reduced by one dose level 
 
5.3 
Cyclophosphamide 
 
5.3.1 
Hematuria  
Omit in the presence of macroscopic hematuria. If there is a history of previous 
significant hematuria, hydrate before cyclophosphamide until specific gravity is 
< 1.010 and hydrate at 125 mL/m2/hr for 24 hours after dose. If mesna was initially 
given in 3 separate boluses, change administration to continuous IV infusion. The 
continuous infusion should be started 15-30 minutes before or at the same time as 
cyclophosphamide and finished no sooner than 8 hours after the end of 
cyclophosphamide infusion. If the patient develops hematuria while receiving 
mesna continuous IV infusion at 60% dosing, increase mesna dosing to 100% of 
the cyclophosphamide dose. If hematuria persists with 100% mesna administration 
by continuous infusion, omit remaining doses during that cycle. 
 
5.3.2 
Renal Dysfunction  
If creatinine clearance or radioisotope GFR is < 10 mL/min/1.73 m2, reduce dose 
of cyclophosphamide by 50%. Prior to dose adjustment of cyclophosphamide, the 
creatinine clearance should be repeated with good hydration. 
 
5.4 
Dexamethasone 
 
5.4.1 
Hypertension  
Dose should not be reduced. Sodium restriction and anti-hypertensives should be 
employed in an effort to control hypertension. Avoid calcium channel blockers due 
to their potential prohemorrhagic effect. 
 
5.4.2 
Hyperglycemia  
Dose should not be reduced for hyperglycemia. Rather, insulin therapy should be 
employed to control the blood glucose level. 
 
5.4.3 
Pancreatitis  
Do not modify dose for asymptomatic elevations of amylase and/or lipase. 
Discontinue steroids, except for stress doses, in the presence of hemorrhagic 
pancreatitis or severe pancreatitis. 
 
5.4.4 
Varicella  
Steroids should be held during active infection except during Cycles 1 and 2. Do 
not hold during incubation period following exposure. 
 
5.4.5 
Inability to use oral doses  
For dexamethasone, substitute the IV preparation mg for mg. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
52 
 
5.5 
Doxorubicin 
 
5.5.1 
Cardiac Toxicity  
If prolongation of the QTc interval (> 0.48 sec.), or a decrease in the shortening 
fraction to < 27% is observed, the doxorubicin-containing chemotherapy should 
be postponed 1 week, any existing malnutrition corrected and the tests repeated. If 
the abnormalities persist, doxorubicin should be discontinued. 
 
5.5.2 
Hyperbilirubinemia  
If direct bilirubin is between 1.2 mg/dL and 3 mg/dL, give 50% of the dose, if 
between 3.1 mg/dL and 5 mg/dL, give 25% of the dose, and if > 5 mg/dL omit 
dose. 
 
5.5.3 
Mucositis  
If patient has severe infection or severe mucositis (Grade 3-4), may delay start of 
cycle. Doses should be given at full dose.  
 
5.6 
Etoposide 
 
5.6.1 
Allergic Reaction  
Premedicate with diphenhydramine (1-2 mg/kg slow IV push, maximum dose is 
50 mg; if unavailable, other H1 antagonists may be used as appropriate). If 
symptoms persist, add hydrocortisone 100-300 mg/m2. Continue to use 
premedication before etoposide in the future. Also consider substituting an 
equimolar amount of etoposide phosphate, in the face of significant allergy and/or 
hypotension. Etoposide phosphate is a water soluble prodrug that does not contain 
polysorbate 80 and polyethyleneglycol, the solubilizing agent in etoposide that 
may induce allergic reactions and hypotension. Etoposide phosphate is rapidly 
converted to etoposide in vivo and provides total drug exposure, as represented by 
AUC (0-infinity) that is statistically indistinguishable from that measured for 
etoposide at equimolar doses. 
 
5.6.2 
Hypotension  
If diastolic or systolic blood pressure (BP) falls 20 mm Hg during infusion, reduce 
infusion rate by 50%. Start a simultaneous infusion of NS 10 mL/kg if BP fails to 
recover or falls further. Stop infusion if BP does not recover, continue NS. If the 
patient has had any episode of hypotension, prehydrate with 0.9% NaCl at 
10 mL/kg/hr for 2 hours prior to any subsequent infusion. 
 
5.6.3 
Renal Insufficiency  
If renal function decreases, adjust etoposide as follows: CrCl/GFR 10-50 
mL/min/1.73 m2, decrease dose by 25%; if CrCl/GFR < 10 mL/min/1.73 m2, 
decrease dose by 50%.  
 
5.6.4 
Hyperbilirubinemia  
If direct bilirubin is > 2 mg/dL, decrease dose by 50%. If direct bilirubin 
is > 5 mg/dL, hold etoposide. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
53 
 
5.7 
Ifosfamide 
 
5.7.1 
Hematuria 
Omit in the presence of macroscopic hematuria. If there is a history of previous 
significant hematuria, hydrate before ifosfamide until specific gravity is < 1.010 
and hydrate at 125 mL/m2/hr for 24 hours after dose. If mesna was initially given 
in 3 separate boluses, change administration to continuous IV infusion. The 
continuous infusion should be started 15-30 minutes before or at the same time as 
ifosfamide and finished no sooner than 8 hours after the end of ifosfamide infusion. 
If the patient develops hematuria while receiving mesna continuous IV infusion at 
60% dosing, increase mesna dosing to 100% of the ifosfamide dose. If hematuria 
persists with 100% mesna administration by continuous infusion, omit remaining 
doses during that cycle. 
 
5.7.2 
Neurotoxicity 
This is an organic brain syndrome, manifestations of which range from mild 
confusion and disorientation to seizures, ataxia, and coma. It may be aggravated 
by impaired renal function, low serum albumin and possibly other conditions such 
as large tumor burden in the pelvis, short infusion times, or prior CNS disease. It 
usually, but does not always, resolve spontaneously; it may or may not recur with 
subsequent doses. Methylene blue has been reported to reverse the ifosfamide-
related-encephalopathy syndrome in some, but not all, patients. If other causes for 
the neurological symptoms have been ruled out and Grade III or greater 
neurotoxicity is present, methylene blue may be administered until symptoms 
improve. Since ifosfamide-induced neurotoxicity may not recur, ifosfamide 
therapy may be continued with the next scheduled cycle. 
 
5.7.3 
Nephrotoxicity 
If estimated CrCl/GFR is < 50 mL/min/1.73 m2 and the patient is well-hydrated, 
defer ifosfamide containing chemotherapy for 1 week. If after a 1 week delay the 
estimated CrCl/GFR is still < 50 mL/min/1.73 m2 (in a well-hydrated patient), hold 
ifosfamide. Estimated creatinine clearance should be repeated with good 
hydration. A timed, 24 hour urine collection for creatinine clearance or 
radionuclide GFR should be performed to confirm renal dysfunction 
 
5.8 
Methotrexate 
 
5.8.1  Nephrotoxicity 
For patients with CrCl/GFR < 60 mL/min/1.73 m2, delay further courses of 
methotrexate until CrCl/GFR ≥ 60 mL/min/1.73 m2. 
 
5.8.2  Hepatic Toxicity 
ALT or AST < 20 times normal give full dose. ALT or AST ≥ 20 times normal of 
upper limits, check every 48 hours until < 10 times normal, then give full dose. If 
not recovered by 1 week after cycle is due, hold methotrexate. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
54 
 
6.0 
DRUG INFORMATION  
Please see Appendix VI for drug interactions associated with the drugs used in this study. 
 
6.1 
Brentuximab vedotin                                                                                        
11/09/15 
(SGN35, AdcetrisTM, NSC#749710) 
 
6.1.1 
Structure and molecular weight  
Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) 
consisting of three components: the chimeric IgG1 antibody cAC10, specific for 
human CD30, the microtubule disrupting agent MMAE, and a protease-cleavable 
linker that covalently attaches MMAE to cAC10. Approximately 4 molecules of 
MMAE are attached to each antibody molecule. Brentuximab vedotin is produced 
by chemical conjugation of the antibody and small molecule components. The 
antibody is produced by mammalian (Chinese hamster ovary) cells, and the small 
molecule components are produced by chemical synthesis. Brentuximab vedotin 
has an approximate molecular weight of 153 kDa. 
 
6.1.2 
Supplied by 
Seattle Genetics, Inc. and the Division of Cancer Treatment and Diagnosis 
(DCTD), NCI. Do NOT use commercial supply. 
 
6.1.3 
Formulation 
The agent is supplied as a sterile, white to off-white preservative-free lyophilized 
cake or powder in individually-boxed single-use vials containing 50 mg 
brentuximab vedotin per vial. 
 
6.1.4 
Storage 
Store vial dry under refrigeration at 2-8°C (36-46°F) in the original carton to 
protect from light until reconstitution and use. 
 
6.1.5 
Solution Preparation 
Use appropriate aseptic technique for reconstitution and preparation of dosing 
solutions. 
 
Please note that the dose for patients weighing greater than 100 kg should be 
calculated based on a weight of 100 kg. 
Preparation consists of 2 steps: dilution of the stock solution and dilution of the final 
solution. 
Step 1: Make a 5 mg/mL concentration. Use vials from the same Lot number 
for each dose. 
1. Reconstitute the 50 mg lyophilized powder brentuximab vedotin with 
10.5 mL Sterile Water for Injection, USP. Final concentration is 5 mg/mL 
(Note: total volume is 11 mL). 
2. Swirl the vial gently. Do not shake. 
3. Let the reconstituted vial settle for one minute to eliminate bubbles. The 
reconstituted solution should be colorless, clear to slightly opalescent and 
should NOT have visible particulates. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
55 
 
4. Store the reconstituted vial under refrigeration (2° – 8° C) and protect from 
light if not used immediately. Discard after 8 hours. 
Step 2: Further dilute the IV solution. 
1. Withdraw the calculated amount of drug from the 5 mg/mL reconstituted vial 
in step 1. 
2. Inject the required amount of drug into 0.9% NS, Lactated Ringer’s Solution, 
USP, or dextrose 5% in Water (D5W), USP to a final concentration between 
0.4 – 1.8 mg/mL.  
3. Brentuximab vedotin solution is compatible in polyvinylchloride (PVC), 
ethylene vinyl acetate (EVA), polyolefin, or polyethylene. 
4. Do not shake. Gently invert the bag (or syringe) to mix. 
5. The prepared IV bag (or syringe) is to be stored at refrigeration (2° – 8° C) 
and must be used within 24 hours of initial product reconstitution (or sooner 
per institutional practice for agents without a preservative). Protect the 
prepared IV solution from direct sunlight if not used immediately. 
6. Prior to administration, inspect the IV bag (or syringe) for discoloration or 
floating particulates. Do not use the IV solution if the solution is discolored 
or/and have particulates. 
 
6.1.6 
Stability  
The stability testing of the intact vials is ongoing. Reconstituted agent must be 
diluted and administered within 24 hours. 
CAUTION: The single-use lyophilized dosage form contains no antibacterial 
preservatives. Therefore, the reconstituted product (from Step 1) should be 
discarded within 8 hours after initial entry/puncture. 
 
6.1.7 
Administration 
Infuse the prepared IV solution over 30 minutes. Do not mix with other 
medications. Do not administer as an IV push or bolus. Do not use an in-line filter 
for the IV administration. The IV bag (or syringe) does NOT need light protection 
during the IV administration. 
 
6.1.8 
Potential drug interactions: 
In vitro data indicates that the active metabolite of brentuximab vedotin, 
monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4 but 
is neither a sensitive substrate nor a strong inhibitor/inducer of CYP3A4. However, 
patients should be monitored for potential drug-interaction when administered 
drugs known to be a strong CYP 3A4 inhibitor/inducer with brentuximab vedotin. 
In vitro, MMAE is a substrate of P-gp transporter and is not an inhibitor of P-gp. 
See Appendix IV for a list of CYP3A4 inducers and inhibitors. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
56 
 
6.1.9 
Patient Care Implications 
• 
New signs and symptoms of CNS system abnormalities may indicate 
progressive multifocal leukoencephalopathy (PML). 
• 
Tumor lysis syndrome, particularly in patients with highly proliferative 
tumors or high tumor burden prior to treatment. 
• 
Infusion-related reactions, including anaphylaxis, may occur. 
• 
Signs and symptoms of peripheral neuropathy may include tingling or 
numbness of the hands, feet, or any muscles weakness. 
• 
Steven-Johnson syndrome. 
• 
High fever (≥ 100.5° F) or other signs of potential infection. 
 
6.1.10 Toxicity 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for SGN-
35 (brentuximab vedotin, NSC 749710) 
 
The arm using SGN-35 (brentuximab vedotin, NSC 749710) is closed to 
accrual and treatment.  The CAEPR is no longer being updated.  
 
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/aeguide
lines.pdf for further clarification. Frequency is provided based on 555 patients. 
Below is the CAEPR for SGN-35 (brentuximab vedotin). 
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 2.3, October 2, 20151 
 
 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 4.0 Term) 
[n= 555] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
57 
 
 
 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 4.0 Term) 
[n= 555] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Blood and lymphatic system disorders 
- Other (lymphadenopathy) 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
Fever 
 
 
 Fever (Gr 2) 
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary 
disorders 
- 
Other (hepatotoxicity)2 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infections and infestations - Other 
(herpes zoster) 
 
  
 
Lung infection 
 
  
Upper respiratory infection 
 
 
 Upper respiratory infection (Gr 2) 
INVESTIGATIONS 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 2) 
 
Platelet count decreased 
 
  
 
Weight loss 
 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
  
 
Bone pain 
 
  
 
Musculoskeletal and connective tissue 
disorder - Other (muscle spasms) 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 2) 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
58 
 
 
 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 4.0 Term) 
[n= 555] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Nervous system disorders - 
Other (progressive multifocal 
leukoencephalopathy) 
  
 
Paresthesia 
 
  
 
Peripheral motor neuropathy 
 
 Peripheral motor neuropathy (Gr 2) 
Peripheral sensory neuropathy  
 
 Peripheral sensory neuropathy (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Depression 
 
  
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
 
 
Respiratory, 
thoracic 
and 
mediastinal disorders - Other 
(pulmonary toxicity)3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
  
 
Hyperhidrosis 
 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
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. 
 
2Hepatotoxicity may manifest as increased ALT/AST, bilirubin, alkaline phosphatase, and/or GGT. 
 
3Pulmonary toxicity, which may manifest as pneumonitis, interstitial lung disease, or adult respiratory distress 
syndrome (ARDS), has been observed in patients treated in brentuximab vedotin monotherapy trials as well as in 
combination with bleomycin. 
 
Adverse Events also reported on SGN-35 (brentuximab vedotin) trials but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that SGN-35 (brentuximab vedotin) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Myocardial infarction; Pericardial effusion; Sinus tachycardia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Infusion related reaction; Non-
cardiac chest pain 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (oral candidiasis); Meningitis; 
Pharyngitis; Sepsis; Sinusitis; Skin infection; Urinary tract infection 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Investigations - 
Other (blood LDH increased); Lymphocyte count decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; Hyperkalemia; 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
59 
 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle weakness; Myositis; 
Neck pain 
NEOPLASMS BENIGN, MALIGNANT, AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Myelodysplastic syndrome 
NERVOUS SYSTEM DISORDERS - Dysesthesia; Encephalopathy; Seizure; Syncope 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (pyelonephritis) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - Other 
(groin pain) 
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome3; 
Pleural effusion3; Pneumothorax3; Productive cough; Respiratory, thoracic and mediastinal disorders - Other 
(oropharyngeal pain) 
VASCULAR DISORDERS - Hot flashes; Hypertension; Hypotension; Thromboembolic event 
 
 
Note: SGN-35 (brentuximab vedotin) 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. 
 
 
6.1.11 Clinical Drug Request 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the PMB 
Online Agent Order Processing (OAOP) application at 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://ctepcore.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. 
 
6.1.12 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 (DAR) Form. (See the 
CTEP home page at http://ctep.cancer.gov for the Procedures for Drug 
Accountability and Storage and to obtain a copy of the DARF and Clinical Drug 
Request form). 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
60 
 
6.2 
Crizotinib 
01/23/2019 
(XALKORI®, PF-02341066, PF-02341066-004) NSC# 749005) 
 
6.2.1 
Structure and molecular weight  
The chemical name for the drug substance is (R)-3-[1-(2,6-Dichloro-3-fluoro-
phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine. 
 
The structure of crizotinib is shown in the diagram below: 
 
 
 
Molecular Weight: 450.34 Daltons 
 
6.2.2 
Supplied by 
For US sites: Division of Cancer Treatment and Diagnosis (DCTD), NCI. Do NOT 
use commercial supply. 
 
6.2.3 
Formulation 
Capsules will be used in this study. The capsules are available in strengths of 
200 mg and 250 mg. 
 
6.2.4 
Storage 
The capsules should be stored according to labeled conditions. Medication should 
be kept in a secured locked area at the study site in accordance with applicable 
regulatory requirements. Returned medication should be stored separately from 
medication that needs to be dispensed.  
 
6.2.5 
Handling 
Crizotinib must be handled and administered with care.  
 
To minimize exposure, patients should be instructed to keep their medication in 
the bottles provided to them by the study site. Bottles dispensed by the study site 
should be labeled in accordance with the appropriate regulatory requirements. 
Study site staff should provide guidance to patients and/or patient caregivers on 
safe handling practices. 
 
6.2.6 
Stability 
Crizotinib should be stored according to the labeled conditions. To minimize 
exposure, patients should be instructed to keep their medication in its original 
container and stored according to the labeled conditions. 
 
O 
Cl 
Cl 
F 
N 
NH2 
N 
N 
NH 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
61 
 
6.2.7 
Administration 
General Information: 
Crizotinib is given orally and may be administered on an outpatient basis. Patients 
should be instructed to take their medication at approximately the same time each 
day and to not take more than the prescribed dose at any time. The dose may be 
taken with or without food or beverage. If a dose is missed or forgotten at the due 
time, it can be taken up to (but not greater than) 6 hours later to help prevent missed 
doses. If a patient inadvertently takes 1 extra dose during a day, the patient should 
not take the next dose of crizotinib. If a patient vomits after a dose of crizotinib, 
that dose will not be repeated; wait until the next scheduled time to administer a 
dose. Crizotinib is a substrate for and moderate inhibitor of CYP3A4/5; refer to 
Appendix IV for information regarding concomitant medication restrictions. 
 
Oral capsules 
Swallow capsules whole (do not crush, dissolve, or open capsules). May be 
administered with or without food. 
 
6.2.8 
Toxicity  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Crizotinib (PF-02341066, NSC 749005) 
 
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.pdf for further clarification. Frequency is provided based on 2058 patients. Below is 
the CAEPR for Crizotinib (PF-02341066). 
 
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 2.3, October 30, 20181 
 
 Adverse Events with Possible  
 Relationship to Crizotinib (PF-02341066) 
 (CTCAE 5.0 Term) 
[n= 2058] 
 
  
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
Sinus bradycardia 
 
  
ENDOCRINE DISORDERS 
  
 
 
Testosterone deficiency 
  
EYE DISORDERS 
  


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
62 
 
 
 Adverse Events with Possible  
 Relationship to Crizotinib (PF-02341066) 
 (CTCAE 5.0 Term) 
[n= 2058] 
 
  
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Eye disorders - Other (vision 
disorders)2 
 
 
 Eye disorders - Other (vision 
disorders)2 (Gr 2) 
Periorbital edema 
 
 
 Periorbital edema (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colonic perforation 
  
Constipation 
 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
  
 
 
Esophageal ulcer 
  
 
 
Esophagitis 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Edema face 
 
 
 Edema face (Gr 2) 
Edema limbs 
 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
Generalized edema 
 
 
 Generalized edema (Gr 2) 
Localized edema 
 
 
 Localized edema (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
 
 
Hepatobiliary disorders - Other 
(hepatotoxicity) 
  
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory infection 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine 
aminotransferase 
increased (Gr 2) 
 
Alkaline phosphatase increased 
 
  
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 2) 
 
 
Blood bilirubin increased 
  
 
Creatinine increased 
 
  
 
 
Electrocardiogram QT corrected 
interval prolonged 
  
 
Lymphocyte count decreased 
 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle cramp 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
63 
 
 
 Adverse Events with Possible  
 Relationship to Crizotinib (PF-02341066) 
 (CTCAE 5.0 Term) 
[n= 2058] 
 
  
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Headache 
 
  
 
Nervous system disorders - Other 
(neuropathy)3 
 
 Nervous system disorders - Other 
(neuropathy)3 (Gr 2) 
 
 
Syncope 
  
RENAL AND URINARY DISORDERS 
  
 
 
Renal and urinary disorders - Other 
(renal cyst) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash4 
 
  
 
 
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. 
 
2Vision disorders may include the following: Chromatopsia, Diplopia, Halo vision, Photophobia, Photopsia, Vision 
blurred, Visual acuity reduced, Visual brightness, Visual impairment, Vitreous floaters, and Visual perseveration. 
 
3Neuropathy may include the following:  Acute polyneuropathy, Amyotrophy, Areflexia, Autoimmune neuropathy, 
Autonomic failure syndrome, Autonomic neuropathy, Axonal neuropathy, Biopsy peripheral nerve abnormal, Burning 
feet syndrome, Burning sensation, Decreased vibratory sense, Demyelinating polyneuropathy, Dysesthesia, 
Electromyogram abnormal, Formication, Gait disturbance, Genital hypoesthesia, Guillain-Barre syndrome, 
Hyperesthesia, Hypoesthesia, Hyporeflexia, Hypotonia, Ischemic neuropathy, Loss of proprioception, Miller Fisher 
syndrome, Mononeuritis, Mononeuropathy, Mononeuropathy multiplex, Motor dysfunction, Multifocal motor 
neuropathy, Muscle atrophy, Muscular weakness, Myelopathy, Nerve conduction studies abnormal, Nerve 
degeneration, Neuralgia, Neuritis, Neuromuscular toxicity, Neuromyopathy, Neuropathy peripheral, Neuropathy 
vitamin B6 deficiency, Neurotoxicity, Paresthesia, Peripheral motor neuropathy, Peripheral nerve lesion, Peripheral 
nerve palsy, Peripheral nervous system function test abnormal, Peripheral sensorimotor neuropathy, Peripheral 
sensory neuropathy, Peroneal muscular atrophy, Peroneal nerve palsy, Phrenic nerve paralysis, Polyneuropathy, 
Polyneuropathy chronic, Polyneuropathy idiopathic progressive, Radiation neuropathy, Sensorimotor disorder, 
Sensory disturbance, Sensory loss, Skin burning sensation, Temperature perception test decreased, Tinel’s sign, Toxic 
neuropathy, and Ulnar neuritis. 
 
4Treatment-related rash may include erythematous rash, rash maculo-papular, and pruritus. 
 
Adverse events reported on crizotinib (PF-02341066) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that crizotinib (PF-02341066) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other (basophilia); 
Disseminated intravascular coagulation; Eosinophilia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Myocarditis; Pericardial effusion; 
Supraventricular tachycardia 
EYE DISORDERS - Cataract; Optic nerve disorder; Papilledema 
GASTROINTESTINAL DISORDERS - Colitis; Dysphagia; Gastric ulcer; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (gastrointestinal amyloidosis); Ileus 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
64 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Fever; General disorders and 
administration site conditions - Other (failure to thrive); Malaise; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (cholestasis); Hepatobiliary disorders - Other 
(hepatitis) 
IMMUNE SYSTEM DISORDERS - Autoimmune disorder 
INFECTIONS AND INFESTATIONS - Abdominal infection; Infections and infestations - Other (peridiverticular 
abscess); Kidney infection; Lung infection; Sepsis; Skin infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and procedural 
complications - Other (traumatic lung injury); Spinal fracture; Wound complication 
INVESTIGATIONS - Blood lactate dehydrogenase increased; CPK increased; GGT increased; Investigations - Other 
(monocyte count increased); Investigations - Other (platelet count increased); Platelet count decreased 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hyperglycemia; 
Hyperkalemia; 
Hypermagnesemia; Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Musculoskeletal and 
connective tissue disorder - Other (myopathy); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment 
related secondary malignancy; Tumor hemorrhage 
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Ischemia cerebrovascular; Pyramidal tract 
syndrome; Seizure; Stroke 
PREGNANCY, PUERPERIUM AND PERINATAL CONDITIONS - Pregnancy loss 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Euphoria 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Renal calculi; Urinary retention 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Dyspnea; 
Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (pneumomediastinum); 
Respiratory, thoracic and mediastinal disorders - Other (respiratory distress) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Skin and subcutaneous tissue disorders - Other (drug 
eruption) 
VASCULAR DISORDERS - Hematoma; Hypotension; Phlebitis; Thromboembolic event; Vasculitis 
 
 
Note: Crizotinib (PF-02341066) 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. 
 
6.2.9 
Agent Ordering and Agent Accountability 
NCI supplied agents may be requested by the responsible 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), Biosketch, Agent Shipping Form, and Financial 
Disclosure Form (FDF). If there are several participating investigators at one 
institution, CTEP supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
6.2.10 Clinical Drug Request 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the PMB 
Online Agent Order Processing (OAOP) application at https://eapps-


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
65 
 
ctep.nci.nih.gov/OAOP/pages/login.jspx. 
Access 
to 
OAOP 
requires 
the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.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. 
 
6.2.11 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 (DAR) Form. (See the 
CTEP home page at http://ctep.cancer.gov for the Procedures for Drug 
Accountability and Storage and to obtain a copy of the DARF and Clinical Drug 
Request form). 
 
6.3 
CYCLOPHOSPHAMIDE - INJECTION 
 
 
 
(03/13/13) 
(Cytoxan) NSC #26271  
 
 
 
 
 
 
 
 
 
Source and Pharmacology:  
Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is 
inactive until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in 
the liver to active compounds. The initial product is 4-hydroxycyclophosphamide (4-HC) 
which is in equilibrium with aldophosphamide which spontaneously releases acrolein to 
produce phosphoramide mustard. Phosphoramide mustard, which is an active bifunctional 
alkylating species, is 10 times more potent in vitro than is 4-HC and has been shown to 
produce interstrand DNA cross-link analogous to those produced by mechlorethamine. 
Approximately 70% of a dose of cyclophosphamide is excreted in the urine as the inactive 
carboxyphosphamide and 5-25% as unchanged drug. The plasma half-life ranges from 4.1 to 
16 hours after IV administration.  
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children  
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Anorexia, nausea & 
vomiting 
(acute and delayed) 
Abdominal discomfort, 
diarrhea 
Transient blurred vision, nasal 
stuffiness with rapid 
administration, arrhythmias 
(rapid infusion), skin rash, 
anaphylaxis, SIADH 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L) 
Cardiac toxicity with high dose 
(acute – CHF hemorrhagic 
myocarditis, myocardial 
necrosis) (L), 
hyperpigmentation, nail 
changes, impaired wound 
healing, infection secondary to 
immune suppression 
Delayed: 
Any time later 
during therapy 
Gonadal dysfunction: 
azoospermia or 
oligospermia (prolonged or 
permanent)1 (L) 
Amenorrhea1 
Gonadal dysfunction: ovarian 
failure1 (L), interstitial 
pneumonitis, pulmonary 
fibrosis2 (L)  


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
66 
 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy (ALL, 
ANLL, AML), bladder 
carcinoma (long term use > 2 
years), bladder fibrosis  
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination 
with other antineoplastic agents) have been noted in humans. Toxicities include: 
chromosomal abnormalities, multiple anomalies, pancytopenia, and low birth weight. 
Cyclophosphamide is excreted into breast milk. Cyclophosphamide is contraindicated 
during breast feeding because of reported cases of neutropenia in breast fed infants and 
the potential for serious adverse effects. 
1 Dependent on dose, age, gender, and degree of pubertal development at time of treatment. 
2 Risk increased with pulmonary chest irradiation and higher doses. 
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Cyclophosphamide for injection is available as powder for injection or lyophilized powder 
for injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium 
bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains 
75 mg mannitol/100 mg cyclophosphamide. Storage at or below 25ºC (77ºF) is 
recommended. The product will withstand brief exposures to temperatures up to 30ºC 
(86ºF). 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
Cyclophosphamide for Injection: If the drug will be administered as undiluted drug at the 
20 mg/mL concentration, then reconstitute to 20 mg/mL with NS ONLY to avoid a 
hypotonic solution. If the drug will be further diluted prior to administration, then first 
reconstitute with NS, SWFI, or Bacteriostatic Water for Injection (paraben preserved only) 
to a concentration of 20 mg/mL. Following reconstitution further dilute in dextrose or 
saline containing solutions for IV use.  
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information  
 
6.4 
CYTARABINE  
 
 
 
 
 
 
  
(Cytosine arabinoside, Ara-C, Cytosar®) NSC #63878  
 
      (07/13/15) 
 
Source and Pharmacology: 
Cytarabine appears to act through the inhibition of DNA polymerase. A limited, but 
significant, incorporation of cytarabine into both DNA and RNA has also been reported. It 
exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) 
and under certain conditions blocking the progression of cells from the G1 phase to the S-
phase. Cytarabine is metabolized by deoxycytidine kinase and other nucleotide kinases to 
the nucleotide triphosphate (Ara-CTP), an effective inhibitor of DNA polymerase. Ara-
CTP is inactivated by a pyrimidine nucleoside deaminase, which converts it to the nontoxic 
uracil derivative (Ara-U). It appears that the balance of kinase and deaminase levels may 
be an important factor in determining sensitivity or resistance of the cell to cytarabine. It 
has an initial distributive phase t½ of about 10 minutes, with a secondary elimination phase 
t½ of about 1 to 3 hours. Peak levels after intramuscular or subcutaneous administration of 
cytarabine occur about 20 to 60 minutes after injection and are lower than IV 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
67 
 
administration. Intrathecally administered doses are metabolized and eliminated more 
slowly with a t½ of about 2 hours. 
 
Toxicity: (Intravenous, SubQ, IM) 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, 
anorexia 
 
With High Dose: 
conjunctivitis  
Flu-like symptoms with 
fever, rash  
 
Ara-C syndrome (fever, 
myalgia, bone pain, 
occasionally chest pain, 
maculopapular rash, malaise, 
conjunctivitis), anaphylaxis, 
swelling, pain and redness at the 
site of the medication injection 
(SubQ or IM injection) 
 
With High Dose: 
cardiomyopathies (vasculitis, 
and pericarditis), cerebral and 
cerebellar dysfunction 
including: encephalopathy, 
aseptic meningitis, ataxia, 
dysphasia, nystagmus, a 
decreased level of 
consciousness, personality 
changes, somnolence, seizures  
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression 
(anemia, 
thrombocytopenia, 
leukopenia, 
megaloblastosis, 
reticulocytopenia), 
stomatitis, alopecia 
Diarrhea, hypokalemia, 
hypocalcemia, 
hyperuricemia 
 
With High Dose: capillary 
pulmonary leak syndrome 
(RDS, pulmonary edema) 
Hepatotoxicity, sinusoidal 
obstruction syndrome (SOS, 
formerly VOD), urinary 
retention, renal dysfunction, 
pain and erythema of the palms 
and soles 
 
Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
 
 
Asymptomatic nonoliguric 
rhabdomyolysis 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cytarabine have been noted in humans. It is 
unknown whether the drug is excreted in breast milk. 
 
 
Formulation: Cytarabine for Injection is available in vials of 100 mg, 500 mg, 1 g, and 
2 g containing a sterile powder for reconstitution. It is also available at a 20 mg/mL 
concentration with benzyl alcohol (25 mL per vial) or as a preservative free solution (5 mL, 
50 mL per vial), and at a 100 mg/mL concentration with benzyl alcohol (20 mL vial) or as 
preservative free solution (20 mL vial). Hydrochloric acid and/or sodium hydroxide may 
be added to adjust the pH. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-
86°F). Cytarabine solutions should be protected from light. 
 
Guidelines for Administration: See Treatment and Dose Modifications section of the 
protocol. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
68 
 
IV Infusion: 
Reconstitute the lyophilized powder with Bacteriostatic Water for Injection or NS injection. 
Solution containing bacteriostatic agent should not be used for the preparation of 
doses > 200 mg/m2. May be further diluted with dextrose or sodium chloride containing 
solutions. May give by IV push injection, by IV infusion, or by continuous infusion.  
 
Low Dose (≤ 200 mg/m²/dose): For administration by IV push, reconstitute to a 
concentration of 20-100 mg/mL. 
 
Stability: When reconstituted with Bacteriostatic Water for Injection, cytarabine is stable 
for 48 hours at room temperature. Solutions reconstituted without a preservative should be 
used immediately. Discard if solution appears hazy. Diluted solutions in D5W or NS are 
stable for 8 days at room temperature; however, the diluted cytarabine should be used 
within 24 hours for sterility concerns. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
6.5 
DEXAMETHASONE 
(Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC #34521  
(05/09/11) 
Source and Pharmacology: 
Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid 
effects. Dexamethasone, 0.75 mg, has potent anti-inflammatory activity equivalent to 
approximately 5 mg of prednisone. Glucocorticoids produce widespread and diverse 
physiologic effects on carbohydrate, protein, and lipid metabolism, electrolyte and water 
balance, functions of the cardiovascular system, kidney, skeletal muscle, and the nervous 
systems. Glucocorticoids reduce the concentration of thymus-dependent lymphocytes 
(T-lymphocytes), monocytes, and eosinophils. Glucocorticoids selectively bind to the 
cortisol receptors on human lymphoid cells which are found in larger numbers on leukemic 
lymphoblasts. They also decrease binding of immunoglobulin to cell surface receptors and 
inhibit the synthesis and/or release of interleukins, thereby decreasing T-lymphocyte 
blastogenesis and reducing expansion of the primary immune response. The specific cellular 
mechanisms that act to halt DNA synthesis are thought to be related to inhibition of glucose 
transport or phosphorylation, retardation of mitosis, and inhibition of protein synthesis. 
Elimination half-lives for the following age groups have been reported to be: infants and 
children under 2 years of age: 2.3 to 9.5 hours, 8 to 16 years: 2.82 to 7.5 hours, and adults 
(age not specified): 3 to 6 hours. The biologic half-life is 36-72 hours. It is primarily 
metabolized in the liver and excreted by the kidneys. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
69 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Insomnia, hyperphagia 
Gastritis 
Hyperuricemia 
 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Immunosuppression, 
personality changes (mood 
swings, euphoria, anxiety, 
depression), pituitary-
adrenal axis suppression, 
acne (L) 
Hyperglycemia, facial 
erythema, poor wound 
healing, infections (bacterial, 
fungal, parasitic, viral), 
edema 
Pancreatitis (L), increased 
intraocular pressure (L), 
hypertension, psychosis, 
vertigo, headache 
Delayed: 
Any time later 
during therapy 
Cushing’s syndrome 
(moon facies, truncal 
obesity) 
Striae and thinning of the 
skin, easy bruising, muscle 
weakness, osteopenia  
Spontaneous fractures (L), 
growth suppression, peptic 
ulcer and GI bleeding, 
pseudotumor cerebri 
(increased intracranial 
pressure with papilledema, 
headache), aseptic necrosis 
of the femoral and humeral 
heads (L), urolithiasis1 (L) 
Late: 
Any time after 
completion of 
treatment 
 
Cataracts (which may be 
reversible on discontinuation 
of dexamethasone in 
children) 
 
Unknown 
Frequency and 
Timing: 
Fetal and teratogenic toxicities: dexamethasone crosses the placenta with 54% 
metabolized by enzymes in the placenta. In animal studies, large doses of cortisol 
administered early in pregnancy produced cleft palate, stillborn fetuses, and 
decreased fetal size. Chronic maternal ingestion during the first trimester has shown a 
1% incidence of cleft palate in humans. There are no reports of dexamethasone 
excretion into breast milk in humans; however, it is expected due to its low molecular 
weight that it would partition into breast milk. 
1 Mainly reported in pediatric patients with ALL. Howard SC et al. Urolithiasis in pediatric patients 
with acute lymphoblastic leukemia. Leukemia 2003; 17: 541-6. (L) Toxicity may also occur later. 
Formulation and Stability: 
 
Oral: 
Available in 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg tablets; liquid 
formulations are available in 0.5 mg/5 mL and 1 mg/1 mL concentrations. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include: calcium or 
magnesium stearate, corn starch, lactose, and various dyes. Liquid formulations may include: 
5%-30% alcohol, benzoic acid, sorbitol, sodium saccharin, glycerin, purified water, and 
various dyes.  
 
Injection: 
Dexamethasone Sodium Phosphate Solution for Injection is available as 4 mg/mL (1 mL, 
5 mL, and 30 mL vials) and 10 mg/mL (1 mL and 10 mL vial sizes). Vials are available in 
multi-dose vials as well as unit of use vials and syringes. Inactive ingredients vary depending 
on manufacturer but include creatinine, sodium citrate, sodium hydroxide to adjust pH, 
Water for Injection, sodium sulfite, bisulfite and metabisulfite, methyl and propyl paraben, 
benzyl alcohol, and EDTA. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
70 
 
Guidelines for Administration: See Treatment and Dose Modifications section of the 
protocol. 
 
Dexamethasone Sodium Phosphate for Injection may be given IV, or IM undiluted. For IV 
use, it may be further diluted in dextrose or saline containing solutions. Avoid using benzyl 
alcohol-containing dexamethasone solutions in neonates. Diluted solutions that contain no 
preservatives should be used within 24 hours, but maintain stability for at least 14 days in 
PVC bags at room temperature protected from light. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
6.6 
DOXORUBICIN 
(Adriamycin®) NSC #123127   
 
 
 
 
(05/09/11) 
 
Source and Pharmacology:  
An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. The cytotoxic 
effect of doxorubicin on malignant cells and its toxic effects on various organs are thought 
to be related to nucleotide base intercalation and cell membrane lipid binding activities of 
doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA 
polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable 
complexes appears to be an important mechanism of doxorubicin cytocidal activity. 
Doxorubicin cellular membrane binding may affect a variety of cellular functions. 
Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases, and 
dehydrogenases generate highly reactive species including the hydroxyl free radical (OH•). 
Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu 
(II) and Fe (III) reduction at the cellular level. Cells treated with doxorubicin have been 
shown to manifest the characteristic morphologic changes associated with apoptosis or 
programmed cell death. Doxorubicin-induced apoptosis may be an integral component of 
the cellular mechanism of action relating to therapeutic effects, toxicities, or both. 
Doxorubicin serum decay pattern is multiphasic. 
 
The initial distributive t½ is approximately 5 minutes suggesting rapid tissue uptake of 
doxorubicin. The terminal t½ of 20 to 48 hours reflects a slow elimination from tissues. 
Steady-state distribution volumes exceed 20 to 30 L/kg and are indicative of extensive drug 
uptake into tissues. Plasma clearance is in the range of 8 to 20 mL/min/kg and is 
predominately by metabolism and biliary excretion. The P450 cytochromes which appear 
to be involved with doxorubicin metabolism are CYP2D6 and CYP3A4. Approximately 
40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its 
metabolites appear in the urine during the same time period. Binding of doxorubicin and 
its major metabolite, doxorubicinol, to plasma proteins is about 74 to 76% and is 
independent of plasma concentration of doxorubicin. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
71 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children  
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Nausea, vomiting, pink 
or red color to urine, 
sweat, tears, and saliva 
Hyperuricemia, facial 
flushing, sclerosis of the 
vein 
Diarrhea, anorexia, 
erythematous streaking of the 
vein (flare reaction), 
extravasation (rare) but if 
occurs = local ulceration, 
anaphylaxis, fever, chills, 
urticaria, acute arrhythmias 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia), alopecia  
Mucositis (stomatitis and 
esophagitis), 
hepatotoxicity  
Radiation recall reactions, 
conjunctivitis and lacrimation 
Delayed: 
Any time later 
during therapy 
 
Cardiomyopathy1 (CHF 
occurs in 5-20% at 
cumulative doses 
≥ 450 mg/m²) (L) 
 
Cardiomyopathy1 (CHF 
occurs in < 5% at cumulative 
doses ≤ 400 mg/m²) (L), 
ulceration and necrosis of 
colon, 
hyper-pigmentation of nail 
bed and dermal crease, 
onycholysis 
Late: 
Any time after 
completion of 
treatment 
Subclinical cardiac 
dysfunction 
CHF (on long term 
follow up in pediatric 
patients) 
Secondary malignancy (in 
combination regimens) 
Unknown 
Frequency and 
Timing:   
Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of doxorubicin 
have been noted in animal models. Doxorubicin is excreted into breast milk in 
humans 
1 Risk increases with cardiac irradiation, exposure at a young or advanced age. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 mg¹, 
50 mg¹vials and a preservative-free 2 mg/mL solution in 10 mg¹, 20 mg¹, 50 mg¹, 200 mg² 
vials. 
¹: Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin RDF (rapid 
dissolution formula) also contains methylparaben, 1 mg per each 10 mg of doxorubicin, to enhance 
dissolution. 
² Multiple dose vial contains lactose, 0.9% NS, HCl to adjust pH to 3. 
 
Aqueous Solution: Store refrigerated 2°-8°C, (36°-46°F). Protect from light. Retain in 
carton until contents are used. 
 
Powder for Injection: Store unreconstituted vial at room temperature, 15°-30°C (59°-86°F). 
Retain in carton until contents are used. Reconstitute with preservative-free NS to a final 
concentration of 2 mg/mL. After adding the diluent, the vial should be shaken and the 
contents allowed to dissolve. The reconstituted solution is stable for 7 days at room 
temperature and 15 days under refrigeration, 2°-8°C (36°-46°F) when protected from light. 
Doxorubicin further diluted in 50 – 1000 mL of NS or D5W is stable for up to 48 hours at 
room temperature (25°C) when protected from light. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
72 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol.  
 
Administer IV through the tubing of rapidly infusing solution of D5W or 0.9% NaCl 
preferably into a large vein. Protect the diluted solution from sunlight. To avoid 
extravasation, the use of a central line is suggested. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
6.7 
ETOPOSIDE - INJECTION 
(Toposar®, Etopophos®, VP-16)  NSC #141540 
 
    (11/15/16) 
 
Source and Pharmacology:  
A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase 
II and DNA which results in single and double strand DNA breaks. Its main effect appears 
to be in the S and G2 phase of the cell cycle. The initial t½ is 1.5 hours and the mean terminal 
half-life is 4 to 11 hours. It is primarily excreted in the urine. In children, approximately 
55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance 
of etoposide is 7 to 10 mL/min/m² or about 35% of the total body clearance over a dose 
range of 80 to 600 mg/m². Etoposide, therefore, is cleared by both renal and non-renal 
processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma 
etoposide clearance is not known. Biliary excretion appears to be a minor route of etoposide 
elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. 
Metabolism accounts for most of the non-renal clearance of etoposide. 
 
The maximum plasma concentration and area under the concentration time curve (AUC) 
exhibit a high degree of patient variability. Etoposide is highly bound to plasma proteins 
(~94%), primarily serum albumin. Pharmacodynamic studies have shown that etoposide 
systemic exposure is related to toxicity. Preliminary data suggests that systemic exposure 
for unbound etoposide correlates better than total (bound and unbound) etoposide. There 
is poor diffusion into the CSF < 5%. 
 
Etoposide phosphate is a water soluble ester of etoposide which is rapidly and completely 
converted to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate 
that etoposide phosphate is bioequivalent to etoposide when it is administered in molar 
equivalent doses. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
73 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children  
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting 
Anorexia 
Transient hypotension during 
infusion; anaphylaxis (chills, 
fever, tachycardia, dyspnea, 
bronchospasm, hypotension) 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression (anemia, 
leukopenia), alopecia 
Thrombocytopenia, 
diarrhea, abdominal pain, 
asthenia, malaise, rashes 
and urticaria 
Peripheral neuropathy, 
mucositis, hepatotoxicity, 
chest pain, thrombophlebitis, 
congestive heart failure, 
Stevens-Johnson Syndrome, 
exfoliative dermatitis 
Delayed: 
Any time later during 
therapy 
 
 
Dystonia, ovarian failure, 
amenorrhea, anovulatory 
cycles, hypomenorrhea, 
onycholysis of nails 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy 
(preleukemic or leukemic 
syndromes) 
 
Unknown Frequency 
and Timing:  
Fetal toxicities and teratogenic effects of etoposide have been noted in animals at 
1/20th of the human dose. It is unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability: 
Etoposide for Injection is available as a 20 mg/mL solution in sterile multiple dose vials 
(5 mL, 25 mL, or 50 mL each). The pH of the clear, nearly colorless to yellow liquid is 3 
to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg 
modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) 
alcohol. Vial headspace contains nitrogen. Unopened vials of etoposide are stable until 
expiration date on package at controlled room temperature (20°-25°C or 68°-77°F). 
 
Etoposide phosphate for injection is available for intravenous infusion as a sterile 
lyophilized powder in single-dose vials containing etoposide phosphate equivalent to 
100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide 
phosphate must be stored under refrigeration (2°-8°C or 36°-46°F). Unopened vials of 
etoposide phosphate are stable until the expiration date on the package. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
 
Etoposide: 
Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide infusions 
are stable at room temperature for 96 hours when diluted to concentrations of 0.2 mg/mL; 
stability is 24 hours at room temperature with concentrations of 0.4 mg/mL. The time to 
precipitation is highly unpredictable at concentrations > 0.4 mg/mL. Use in-line filter 
during infusion secondary to the risk of precipitate formation. However, the use of an in-
line filter is not mandatory since etoposide precipitation is unlikely at concentrations of 
0.1-0.4 mg/mL. Do not administer etoposide by rapid intravenous injection. Slow rate 
of administration if hypotension occurs.  
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
74 
 
Leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags occurred 
with etoposide 0.4 mg/mL in NS. To avoid leaching, prepare the etoposide solution as close 
as possible, preferably within 4 hours, to the time of administration or alternatively as per 
institutional policy; glass or polyethylene-lined (non-PVC) containers and polyethylene-
lined tubing may be used to minimize exposure to DEHP. 
 
Etoposide Phosphate: 
Reconstitute the 100 mg vial with 5 or 10 mL of Sterile Water for Injection, D5W, NS, 
Bacteriostatic Water for Injection with Benzyl Alcohol, or Bacteriostatic Sodium Chloride 
for Injection with Benzyl Alcohol for a concentration equivalent to 20 mg/mL or 
10 mg/mL etoposide equivalent (22.7 mg/mL or 11.4 mg/mL etoposide phosphate), 
respectively. Use diluents without benzyl alcohol for neonates and infants < 2 years of 
age or patients with hypersensitivity to benzyl alcohol.  
 
When reconstituted as directed, etoposide phosphate solutions can be stored in glass or 
plastic containers under refrigeration for 7 days. When reconstituted with a diluent 
containing a bacteriostat, store at controlled room temperature for up to 48 hours. 
Following reconstitution with SWFI, D5W, or NS store at controlled room temperature for 
up to 24 hours. 
 
Following reconstitution, etoposide phosphate may be further diluted to a concentration as 
low as 0.1 mg/mL of etoposide with D5W or NS. The diluted solution can be stored under 
refrigeration or at controlled room temperature for 24 hours. 
 
Supplier: Commercially available from various manufacturers. See package insert for more 
detailed information. 
 
CANADIAN SITES 
Etoposide for Injection is available as a 20 mg/mL solution. 
 
Etopophos® (etoposide phosphate) is not commercially available in Canada. Sites may 
purchase and import the USA commercial supply from Bristol Laboratories via an 
International Distributor (Pharma Exports LLC, phone: 1-412-885-3700, fax: 1-412-885-
8022, email: pharexp@aol.com) under the authority of the protocol’s No Objection Letter 
(NOL). Drug Accountability Log (DAL) must record Lot #’s and expiry dates of shipments 
received and doses dispensed. Sites may use their own DAL as long as it complies with all 
elements of ICH GCP and Division 5 of the Food and Drugs Act. Each site is responsible 
for the procurement (import +/- purchase) of Etoposide Phosphate (Etopophos). Sites may 
import and manage a single clinical trial supply for multiple protocols as long as each 
protocol has an NOL and the protocol the patient is registered on is recorded on the DAL. 
 
6.8 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ  
(Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen®, Granix®, 
Zarxio®) NSC #614629  
 
 
 
 
 
(11/15/16)  
 
Source and Pharmacology:  
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by 
recombinant DNA technology. Filgrastim is a 175 amino acid protein with a molecular 
weight of 18,800 daltons manufactured by recombinant DNA technology utilizing E coli 
bacteria into which has been inserted the human granulocyte colony stimulating factor 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
75 
 
gene. It differs from the natural protein in that the N- amino acid is methionine and the protein 
is not glycosylated. G-CSF is a lineage specific colony-stimulating factor, which regulates 
the production of neutrophils within the bone marrow and affects neutrophil progenitor 
proliferation, differentiation, and selected end-cell functional activation (including 
enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory 
burst, antibody dependent killing, and the increased expression of some functions 
associated with cell surface antigens). Filgrastim exhibits nonlinear pharmacokinetics with 
clearance dependent on filgrastim concentration and neutrophil count. Filgrastim is cleared 
by the kidney. The elimination half-life is similar for subcutaneous and intravenous 
administration, approximately 3.5 hours. The time to peak concentration when administered 
subcutaneously is 2-8 hours. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children  
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Local irritation at the 
injection site, headache 
Allergic reactions (more 
common with IV 
administration than subq):skin 
(rash, urticaria, facial edema), 
respiratory (wheezing, 
dyspnea) and cardiovascular 
(hypotension, tachycardia), 
low grade fever  
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Mild to moderate 
medullary bone pain 
Increased: alkaline 
phosphatase, lactate 
dehydrogenase and uric 
acid, thrombocytopenia 
Splenomegaly, splenic 
rupture, rash or exacerbation 
of pre-existing skin rashes, 
sickle cell crises in patients 
with SCD, excessive 
leukocytosis, Sweet’s 
syndrome (acute febrile 
neutrophilic dermatosis) 
Delayed: 
Anytime later 
during therapy 
 
 
Cutaneous vasculitis, ARDS 
Late: 
Anytime after 
completion of 
treatment 
 
 
MDS or AML (confined to 
patients with severe chronic 
neutropenia and long term 
administration) 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. 
Conflicting data exist in animal studies and filgrastim is known to pass the placental 
barrier. It is unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability:  
Neupogen® supplied as a clear solution of 300 mcg/mL in 1 mL or 1.6 mL vials. 
Neupogen® vials are preservative free single use vials. Discard unused portions of open 
vials. 
 
Neupogen®, Granix®, and Zarxio® are also available as single use prefilled syringes 
containing 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim for subcutaneous 
administration.  
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
76 
 
Store refrigerated at 2º-8ºC (36º-46ºF). Protect from light. Do not shake. Prior to injection, 
filgrastim and filgrastim-sndz may be allowed to reach room temperature for a maximum 
of 24 hours (infusion must be completed within 24 hours of preparation). TBO-filgrastim 
may be removed from 2°C-8°C (36°F-46°F) storage for a single period of up to 5 days 
between 23°C to 27°C (73°F to 81°F). Avoid freezing and temperatures > 30ºC.  
 
For IV use, dilute filgrastim (Neupogen®) and tbo-filgrastim (Granix®) in D5W only to 
concentrations >15 mcg/mL. Filgrastim-sndz (Zarxio®) may be diluted in D5W to 
concentrations between 5 mcg/mL and 15 mcg/mL. At concentrations below 15 mcg/mL, 
human serum albumin should be added to make a final albumin concentration of 0.2% 
(2 mg/mL) in order to minimize the adsorption of filgrastim to plastic infusion containers 
and equipment for all 3 products (communication on file from Teva Pharmaceuticals USA). 
Filgrastim or filgrastim-sndz dilutions of 5 mcg/mL or less are not recommended. 
Tbo-filgrastim dilutions below 2 mcg/mL are not recommended. Diluted filgrastim 
biosimilar products should be stored at 2º-8ºC (36º-46ºF) and used within 24 hours. Do not 
shake. 
 
Do not dilute with saline-containing solutions at any time; precipitation will occur. 
 
 
Guidelines for Administration:  
See Treatment, Dose Modifications and Supportive Care sections of the protocol. 
Filgrastim biosimilar products should not be administered within 24 hours of (before AND 
after) chemotherapy. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information  
 
 
6.9 
IFOSFAMIDE 
(Isophosphamide, Iphosphamide, Z4942, Ifex®) NSC #109724   
(05/09/11) 
 
 
 
Source and Pharmacology: 
Ifosfamide is a structural analogue of cyclophosphamide. Ifosfamide requires hepatic 
microsomal activation (P450 3A isoenzymes) for the production of the reactive 4-
hydroxyoxazaphorine intermediate which serves as a carrier molecule for the ultimate 
intracellular liberation of acrolein and phosphoramide mustard which is an active 
bifunctional alkylating species. Acrolein is thought to be the cause of the hemorrhagic cystitis 
as seen with cyclophosphamide. Ifosfamide demonstrates dose-dependent pharmacokinetics 
whereby the terminal half-life ranges from 7 to 16 hours at doses of 1.6-2.4 g/m² to 3.8-
5 g/m², respectively. At 1.6-2.4 g/m²/d, 12 to 18% of the dose was excreted as unchanged 
drug in the urine, whereas at a 5 g/m² single-dose, 61% was excreted in the urine as the parent 
drug. Evidence also exists to suggest that ifosfamide metabolism is inducible, with more 
rapid clearance occurring in the second and later doses when a course of therapy is given as 
fractionated doses over 3 to 5 days. There is more chloroethyl side chain oxidation of 
ifosfamide (up to 50%) than of cyclophosphamide (< 10%), and the degree of such 
metabolism is more variable than with cyclophosphamide. Oxidation of the chloroethyl 
groups produces chloroacetaldehyde, which is thought to be responsible for the 
neurotoxicity and renal toxicity that have been seen with ifosfamide therapy. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
77 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
 out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Nausea & vomiting 
(acute and delayed) 
CNS toxicity 
(somnolence, depressive 
psychosis and confusion) 
Anorexia, diarrhea, 
constipation, 
encephalopathy which may 
progress to coma (L), 
seizure, SIADH, phlebitis, 
hypokalemia 
Prompt: 
Within 2-3 
weeks, prior to 
next course 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, 
anemia, cardiac toxicities 
(arrhythmia, 
asymptomatic ECG 
changes), microscopic 
hematuria, metabolic 
acidosis 
↑ liver enzymes, ↑ bilirubin, 
hemorrhagic cystitis with 
macroscopic hematuria, 
dysuria, cystitis and urinary 
frequency (< 5% with 
mesna and vigorous 
hydration) (L), bladder 
fibrosis 
Delayed: 
Any time later 
during therapy 
Gonadal dysfunction: 
azoospermia or 
oligospermia (prolonged 
or permanent)1 (L) 
 
Renal failure acute or 
chronic, renal tubular 
acidosis, Fanconi-like 
syndrome gonadal 
dysfunction, ovarian 
failure1 (L), CHF 
Late: 
Any time after 
completion of 
treatment 
Moderate nephrotoxicity 
(↓ in glomerular filtration 
rate, renal tubular 
threshold for phosphate, 
and serum bicarbonate) 
 
Secondary malignancy, 
hypophosphatemic rickets  
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of ifosfamide have been noted in animals. 
Ifosfamide is excreted into breast milk. 
1 Dependent on dose, age, gender and degree of pubertal development at time of treatment 
 
 
(L) Toxicity may also occur later. 
 
 
 
Formulation and Stability:  
Ifosfamide is available in 1 g and 3 g single dose vials of lyophilized white powder without 
preservatives and as a 50 mg/mL solution in 20 mL and 60 mL vials.  
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
Reconstitute ifosfamide lyophilized powder with sterile water for injection or bacteriostatic 
water for injection(use 20 mL for the 1 g vial and 60 mL for the 3 g vial) to produce a final 
concentration of 50 mg/mL. Use sterile water for injection without benzyl alcohol for 
neonates and infants < 2 years of age or patients with hypersensitivity to benzyl 
alcohol. Although the reconstituted product is stable for 7 days at room temperature and 
up to 6 weeks under refrigeration, the manufacturer recommends refrigeration and use 
within 24 hours to reduce the possibility of microbial contamination. Store unreconstituted 
vials at room temperature 20°-25°C (68°-77°F). Protect from temperatures above 30°C 
(86° F). Ifosfamide may liquefy at temperatures > 35°C. 
Reconstituted solutions of ifosfamide or ifosfamide solution should be diluted further to 
concentrations of 0.6 to 20 mg/mL in dextrose or saline containing solutions. Such 
admixtures, when stored in large volume parenteral glass bottles, Viaflex bags or PAB 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
78 
 
bags, are physically and chemically stable for 1 week at 30°C (86°F) or 6 weeks at 5°C 
(41°F). The manufacturer recommends refrigeration and use within 24 hours to reduce the 
possibility of microbial contamination. Mesna must always be administered in conjunction 
with ifosfamide. Adequate hydration is required. Achieve urine specific gravity ≤ 1.010 
prior to start of ifosfamide. Refer to the Chemotherapy Administration Guidelines for 
additional information. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information 
 
6.10 
INTRATHECAL TRIPLES   
 
 
 
 
(05/08/12) 
(Methotrexate/Hydrocortisone/Cytarabine, IT-3)  
 
 
 
 
Source and Pharmacology:  
The intrathecal route of administration of a drug produces more consistent CSF drug 
concentrations at relatively smaller doses because of the volume difference between the CSF 
and blood compartments (140 mL vs. 3500 mL in an adult). (The CSF volume of children 
after the first 3 years is equivalent to that of an adult). Drug half-lives are longer as well 
because clearance is related to flow rather than metabolism or protein binding. Intrathecal 
methotrexate has a biphasic elimination curve from the CSF with a t½ of 4.5 and 14 hours 
respectively. Following IT injection of cytarabine the elimination of the drug from the CSF 
is biphasic with a t½ of 1 and 3.4 hours respectively which is 8-fold longer than the clearance 
from plasma. The elimination of hydrocortisone is similarly prolonged. 
 
Intrathecal Triple Therapy (Methotrexate/ Hydrocortisone/Cytarabine) Toxicity:  
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children  
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, fever, 
headache 
Arachnoditis: (headache, 
fever, vomiting, 
meningismus and 
pleocytosis)  
Rash, anaphylaxis (L), paresis, 
bleeding into subarachnoid or 
subdural space (risk > with 
platelet counts < 20,000), 
confusion, fatigue, 
disorientation, seizures 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
 
Myelosuppression, somnolence, 
ataxia, cranial nerve palsy, 
transient and rarely permanent 
paraplegia (L), speech disorders 
Delayed: 
Any time later 
during therapy, 
excluding the 
above condition 
 
Cognitive 
disturbances (L), learning 
disabilities (L) 
Demyelating 
leukoencephalopathy1 (L), 
blindness1  
Late: 
Any time after the 
completion of 
treatment 
 
 
Progressive CNS deterioration1 
1 May be enhanced by systemic therapy such as high dose methotrexate or cytarabine and/or cranial 
irradiation. (L) Toxicity may also occur later. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
79 
 
Formulation and Stability:  
Methotrexate 25 mg/mL preservative free 2 mL vial or methotrexate 20 mg preservative 
free sterile powder for injection vial. Cytarabine 100 mg preservative free sterile powder for 
injection. Hydrocortisone sodium succinate 100 mg vial sterile powder for injection.   
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
 
For intrathecal administration, dilute each agent with 5-10 mL preservative free NS, lactated 
ringers or Elliot’s B solution or as per institutional standard of practice. The volume of CSF 
removed should be equal to at least half the volume delivered. 
 
Of note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric 
delivery, with the patient remaining prone after the procedure may facilitate drug 
distribution. These procedures have not been validated in clinical trials. They are allowed 
but not mandated for patients on COG studies. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
6.11 
LEUCOVORIN CALCIUM   
 
 
 
 
(05/09/11) 
(LCV, Wellcovorin®, citrovorum factor, folinic acid) NSC #003590  
 
 
 
 
Source and Pharmacology: 
Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of 
tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)- l-
isomer, known as Citrovorum factor or (-)-folinic acid. Leucovorin does not require 
reduction by the enzyme dihydrofolate reductase in order to participate in reactions 
utilizing folates as a source of “one-carbon” moieties. Administration of leucovorin can 
counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, 
which act by inhibiting dihydrofolate reductase. In contrast, leucovorin can enhance the 
therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-
fluorouracil. Leucovorin is readily converted to another reduced folate, 5, 10-
methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid 
(an active metabolite of 5-FU) to thymidylate synthase and thereby enhances the inhibition 
of this enzyme. Peak serum levels of 5-methyl THF (an active metabolite) were reached at 
approximately 1.3-1.5 hours (IV/IM) and 2.3 hours for the oral form. The terminal half-life 
of total reduced folates was approximately 6.2 hours. Following oral administration, 
leucovorin is rapidly absorbed and expands the serum pool of reduced folates. At a dose of 
25 mg, almost 100% of the l-isomer (the biologically active form) but only 20% of the d-
isomer is absorbed. Oral absorption of leucovorin is saturable at doses above 25 mg. The 
apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg, and 37% for 
100 mg doses. Both oral and parenteral leucovorin raise the CSF folate levels. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
80 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children 
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
 
Anaphylaxis, urticaria, 
seizure 
Unknown 
Frequency and 
timing: 
Fetal toxicities and teratogenic effects of leucovorin in humans are unknown.  It 
is unknown whether the drug is excreted in breast milk. 
 
 
Formulation and Stability:  
Leucovorin calcium for injection is supplied as a sterile ready to use liquid and a sterile 
powder for injection. The 10 mg/mL preservative free liquid is available in 50 mL vials 
containing sodium chloride 400 mg/vial. Store preservative free liquid in the refrigerator at 
2°-8°C (36°-46°F) protected from light. The powder for injection is available in 50 mg, 
100 mg, 200 mg, and 350 mg vials. Store at room temperature 15°-25°C (59°-77°F) 
protected from light. Reconstitute the sterile powder with sterile water for injection or 
bacteriostatic water for injection to a concentration of 10 mg/mL leucovorin calcium. Do not 
use diluents containing benzyl alcohol for doses >10 mg/m² or in infants < 2 years of age 
or patients with allergy to benzyl alcohol. When Bacteriostatic Water is used, the 
reconstituted solution is good for 7 days. If reconstituted with SWFI, use solution 
immediately as it contains no preservative. One milligram of leucovorin calcium contains 
0.004 mEq of leucovorin and 0.004 mEq of calcium. 
 
The oral form of leucovorin is available as 5 mg, 10 mg, 15 mg, and 25 mg tablets. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include: corn 
starch, dibasic calcium phosphate, magnesium stearate, pregelatinized starch, lactose, 
microcrystalline cellulose, and sodium starch glycolate. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol.  
 
Injection: 
Because of the calcium content of the leucovorin solution, no more than 160 mg of 
leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL solution per 
minute). IV leucovorin and sodium bicarbonate are incompatible. 
 
Oral: 
Oral leucovorin should be spaced evenly (e.g., every six hours) throughout the day and 
may be taken without regard to meals. Doses > 25 mg should be given IV due to the 
saturation of absorption. 
 
Leucovorin should not be administered < 24 hours after intrathecal injections which contain 
methotrexate unless there are special circumstances. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
81 
 
6.12 
MESNA - INJECTION 
  
 
 
 
 
(11/15/16) 
(sodium 2-mercaptoethane sulfonate, UCB 3983, Mesnex) NSC #113891 
 
Source and Pharmacology: 
Mesna was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis 
induced by ifosfamide. Mesna is rapidly oxidized to its major metabolite, mesna disulfide 
(dimesna). Mesna disulfide remains in the intravascular compartment and is rapidly 
eliminated by the kidneys. In the kidney, the mesna disulfide is reduced to the free thiol 
compound, mesna, which reacts chemically with the urotoxic ifosfamide metabolites 
(acrolein and 4-hydroxy-ifosfamide) resulting in their detoxification. The first step in the 
detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a 
nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein 
and to other urotoxic metabolites. In multiple human xenograft or rodent tumor model 
studies, mesna in combination with ifosfamide (at dose ratios of up to 20-fold as single or 
multiple courses) failed to demonstrate interference with antitumor efficacy. 
 
After an 800 mg dose the half lives for mesna and dimesna are 0.36 hours and 1.17 hours, 
respectively. Approximately 32% and 33% of the administered dose was eliminated in the 
urine in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered 
was eliminated within 4 hours.  
 
Toxicity1: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
 
Nausea, vomiting, stomach 
pain, fatigue, headache 
Facial flushing, fever, pain in 
arms, legs, and joints, rash, 
transient hypotension, 
tachycardia, dizziness, anxiety, 
confusion, periorbital swelling, 
anaphylaxis, coughing 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
 
Diarrhea 
 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of mesna have not been noted in animals fed 
10 times the recommended human doses. There are however no adequate and well-
controlled studies in pregnant women. It is not known if mesna or dimesna is excreted 
into human milk 
1All currently available products in the U.S. are preserved with benzyl alcohol. Benzyl Alcohol has 
been associated with death in pre-term infants weighing less than 2500 g and receiving 99-
405 mg/kg/day. Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine 
in the liver, and excreted as hippuric acid. In pre-term infants, however, this metabolic pathway 
may not be well developed. Onset of toxic illness in these infants occurred between several days and 
a few weeks of age with a characteristic clinical picture that included metabolic acidosis 
progressing to respiratory distress and gasping respirations. Many infants also had central-
nervous-system dysfunction, including convulsions and intracranial hemorrhage; hypotension 
leading to cardiovascular collapse was a late finding usually preceding death. [For comparison in 
the ICE regimen of 3000 mg/m²/day of ifosfamide and a daily mesna dose of 60% of the ifosfamide 
dose = to 1800 mg/m²/day; a child would be expected to receive 18 mL/m²/day of mesna 
(concentration of 100 mg/mL and 10.4 mg/mL of benzyl alcohol) 187.2 mg/m²/day of benzyl alcohol 
or 6.24 mg/kg/day.]  
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
82 
 
Formulation and Stability: 
Mesna for injection is available as 100 mg/mL in 10 mL multidose vials which contain 
0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesna Injection 
multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. Store product 
at controlled room temperature 15º-25C (68º-77ºF). Mesna is not light-sensitive, but is 
oxidized to dimesna when exposed to oxygen. Mesna as benzyl alcohol-preserved vials 
may be stored and used for 8 days. 
 
Guidelines for Administration: See Treatment, Dose Modifications, and Supportive Care 
sections of the protocol. 
 
For IV administration, dilute mesna to 20 mg/mL with dextrose or saline containing 
solutions. Mesna may be mixed with ifosfamide or cyclophosphamide. After dilution for 
administration, mesna is physically and chemically stable for 24 hours at 25ºC (77ºF). 
Mesna may cause false positive test for urinary ketones.  
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
CANADIAN SITES 
Preservative-free Mesna is commercially available in Canada from Baxter Corporation 
(Urometixan®); supplied as a 100mg/mL solution which contains edentate disodium and 
sodium hydroxide for pH adjustment, 4 mL and 10 mL single-use ampoules. It is also 
available from Baxter and Fresenius Kabi Canada in multi-dose vials containing 
antibacterial preservatives.   
 
6.13 
METHOTREXATE - IV only  
 
 
 
 
(02/29/12) 
(MTX, amethopterin)  NSC #000740 
 
 
 
 
 
 
 
 
Source and Pharmacology:  
A folate analogue which reversibly inhibits dihydrofolate reductase, the enzyme that reduces 
folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the 
availability of one carbon fragments necessary for the synthesis of purines and the conversion 
of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. The 
polyglutamated metabolites of MTX also contribute to the cytotoxic effect of MTX on DNA 
repair and/or strand breaks. MTX cytotoxicity is highly dependent on the absolute drug 
concentration and the duration of drug exposure. MTX is actively transported across cell 
membranes. At serum methotrexate concentrations exceeding 0.1 µmol/mL, passive 
diffusion becomes a major means of intracellular transport of MTX. The drug is widely 
distributed throughout the body with the highest concentration in the kidney, liver, spleen, 
gallbladder and skin. Plasma concentrations following high dose IV MTX decline in a 
biphasic manner with an initial half-life of 1.5-3.5 hours, and a terminal half life of 
8-15 hours. About 50% is bound to protein. MTX is excreted primarily by the kidneys via 
glomerular filtration and active secretion into the proximal tubules. Renal clearance usually 
equals or exceeds creatinine clearance. Small amounts are excreted in the feces. There is 
significant entero-hepatic circulation of MTX. The distribution of MTX into third-space fluid 
collections, such as pleural effusions and ascitic fluid, can substantially alter MTX 
pharmacokinetics. The slow release of accumulated MTX from these third spaces over time 
prolongs the terminal half-life of the drug, leading to potentially increased clinical toxicity.  
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
83 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children  
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Transaminase elevations 
Nausea, vomiting, 
anorexia 
Anaphylaxis, chills, fever, 
dizziness, malaise, drowsiness, 
blurred vision, acral erythema, 
urticaria, pruritis, toxic epidermal 
necrolysis, Stevens-Johnson 
Syndrome, tumor lysis syndrome, 
seizures1, photosensitivity 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
Myelosuppression, 
stomatitis, gingivitis, 
photosensitivity, fatigue 
Alopecia, folliculitis, acne, renal 
toxicity (ATN, increased 
creatinine/BUN, hematuria), 
enteritis, GI ulceration and 
bleeding, acute neurotoxicity1 
(headache, drowsiness, aphasia, 
paresis, blurred vision, transient 
blindness, dysarthria, hemiparesis, 
decreased reflexes) diarrhea, 
conjunctivitis 
Delayed: 
Any time later 
during therapy, 
excluding the 
above conditions 
 
Learning disability1 (L) 
Pneumonitis, pulmonary fibrosis 
(L), hepatic fibrosis (L), 
osteonecrosis (L), 
leukoencephalopathy1 (L), 
pericarditis, pericardial effusions, 
hyperpigmentation of the nails 
Late: 
Any time after the 
completion of 
therapy 
 
 
Progressive CNS deterioration1 
Unknown 
Frequency and 
Timing: 
Methotrexate crosses the placenta. Fetal toxicities and teratogenic effects of methotrexate 
have been noted in humans. The toxicities include: congenital defects, chromosomal 
abnormalities, severe newborn myelosuppression, low birth weight, abortion, and fetal 
death. Methotrexate is excreted into breast milk in low concentrations. 
1 May be enhanced by HDMTX and/or cranial irradiation. (L) Toxicity may also occur later. 
 
Formulation and Stability:  
Methotrexate for Injection is available as a lyophilized powder for injection in 1000 mg 
vials. The powder for injection contains approximately 7 mEq sodium in the 1000 mg vial. 
Methotrexate for Injection is also available as a 25 mg/mL solution in 2, 4, 8, 10, and 40 mL 
preservative free vials and 2 and 10 mL vials with preservative. The 2, 4, 8, 10, and 40 mL 
solutions contain approximately 0.43, 0.86, 1.72, 2.15, and 8.6 mEq sodium per vial, 
respectively. The preserved vials contain 0.9% benzyl alcohol as a preservative. 
 
Sterile methotrexate powder or solution is stable at 20º-25ºC (68º-77ºF); excursions 
permitted to 15º-30ºC (59º- 86 Fº). Protect from light. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of 
protocol. Leucovorin rescue may be necessary with certain doses of methotrexate. 
For IV use: Powder for injection: Dilute 1000 mg vial with 19.4 mL of preservative free 
SWFI, D5W or NS to a 50 mg/mL concentration. The powder for injection may be further 
diluted in NS or dextrose containing solutions to a concentration of < 25mg/mL for IV use. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
84 
 
 
Do not use the preserved solution for high dose methotrexate administration due to 
risk of benzyl alcohol toxicity. Methotrexate dilutions are chemically stable for at least 
7 days at room temperature but contain no preservative and should be used within 24 hours. 
Diluted solutions especially those containing bicarbonate exposed to direct sunlight for 
periods exceeding 4 hours should be protected from light. 
 
High dose Methotrexate requires alkalinization of the urine, adequate hydration and 
leucovorin rescue. Avoid probenecid, penicillins, cephalosporins, aspirin, proton pump 
inhibitors, and NSAIDS as renal excretion of MTX is inhibited by these agents. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information  
 
6.14 
PEGFILGRASTIM  
 
 
 
 
 
 
(02/10/16) 
(pegylated filgrastim, PEG filgrastim, SD/01, Neulasta®) NSC #725961  
 
 
 
Source and Pharmacology: 
Pegfilgrastim is the pegylated form of recombinant methionyl human G-CSF (filgrastim). 
Pegfilgrastim 
is 
produced 
by 
covalently 
binding 
a 
20-kilodalton 
(kD) 
monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue of 
filgrastim. The molecular weight of pegfilgrastim is 39 kD. G-CSF is a lineage specific 
colony-stimulating factor which regulates the production of neutrophils within the bone 
marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-
cell functional activation (including enhanced phagocytic ability, priming of the cellular 
metabolism associated with respiratory burst, antibody dependent killing, and the increased 
expression of some functions associated with cell surface antigens). 
 
After subcutaneous injection the elimination half-life of pegfilgrastim ranges from 15 to 
80 hours and the time to peak concentration ranges from 24 to 72 hours. Serum levels are 
sustained in most patients during the neutropenic period postchemotherapy, and begin to 
decline after the start of neutrophil recovery, consistent with neutrophil-dependent 
elimination. After subcutaneous administration at 100 mcg/kg in 37 pediatric patients with 
sarcoma, the terminal elimination half-life was 30.1 (+/- 38.2) hours in patients 0 to 5 years-
old, 20.2 (+/- 11.3) hours in patients 6 to 11 years-old, and 21.2 (+/- 16) hours in children 
12 to 21 years-old. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
85 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children  
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
 
Local irritation at the 
injection site (pain, 
induration, and local 
erythema), headache 
Low grade fever, allergic reactions 
(anaphylaxis, angioedema, or 
urticaria), generalized erythema 
and flushing,  
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Mild to moderate 
medullary bone pain 
Increased: alkaline 
phosphatase, lactate 
dehydrogenase and uric 
acid, thrombocytopenia 
Splenomegaly, splenic rupture,  
sickle cell crises in patients with 
sickle cell disease (SCD), 
excessive leukocytosis, Sweet's 
syndrome (acute febrile 
neutrophilic dermatosis) 
Delayed: 
Anytime later 
during therapy 
 
 
ARDS 
Unknown 
frequency and 
timing: 
Fetal toxicities and teratogenic effects of pegfilgrastim in humans are unknown. 
Conflicting data exist in animal studies. It is unknown whether the drug is excreted in 
breast milk. 
 
Formulation and Stability: 
Supplied as a preservative-free solution containing 6 mg (0.6 mL) of pegfilgrastim 
(10 mg/mL) in a single-dose syringe with 27 g, ½ inch needle with an UltraSafe® Needle 
Guard. The needle cover of the prefilled syringe contains drug natural rubber (a derivative 
of latex). Store refrigerated at 2º-8ºC (36º-46ºF) and in the carton to protect from light. 
Prior to injection, pegfilgrastim may be allowed to reach room temperature protected from 
light for a maximum of 48 hours. Avoid freezing. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
Pegfilgrastim should not be administered in the period between 2 weeks before and 
24 hours after chemotherapy. Do not shake. The manufacturer does not recommend use of 
the 6-milligram (mg) fixed-dose formulation of pegfilgrastim in infants, children, or 
adolescents under 45 kilograms. 
 
Supplier: Commercially available. See package insert for further information. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
86 
 
 
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. If PET scan shows uptake at a site that was not imaged by CT or MRI 
scanning, a CT or MRI scan of this site is recommended. Obtain other studies prior to 
start of cycle unless otherwise indicated. 
 
STUDIES TO BE OBTAINED 
Baseline 
Prophase, 
Cycle 1 & 2 
End of 
Cycle 2 
Cycles 3,4,5 & 6 
End of 
Cycle 4 
End of Therapy 
(End of Cycle 6) 
History 
X 
X 
 
X 
 
X 
Physical Exam (Ht, Wt, BSA, Vital 
Signs) 
X 
Weekly 
 
X 
 
X 
Pregnancy Test1; Uric Acid, LDH 
X 
 
 
 
 
 
Performance Status 
X 
X 
 
X 
 
X 
CBC, differential, platelets 
X 
Weekly 
 
Prior to each cycle, 
then weekly 
 
X 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
 
X 
 
X 
Cr, Bilirubin, AST (SGOT), ALT (SGPT) 
X 
X 
 
X 
 
X 
Total protein, Albumin 
X 
 
 
 
 
X 
Urinalysis 
X 
X 
 
X 
 
 
Bone Marrow Aspirate/Biopsy (Bilateral) 
X 
 
X2 
 
 
 
CSF 
X 
 
 
 
 
 
Echocardiogram and EKG 
X 
 
 
X3 
 
X 
CXR (PA + Lateral) 
X 
 
X5 
 
X5 
X 
CT or MRI (primary site and 
neck/chest/abd/pelvis)  
X 
 
X5 
 
X5 
X 
Bone Scan (For patients with bone 
primary disease only) 
X 
 
X5 
 
X5 
X 
FDG-PET Scan (highly recommended - 
not mandatory) 
X 
 
X5 
 
X5 
X4 
Blood for MRD 
X 
X6 
 
 
 
 
1 Women of childbearing potential require a negative pregnancy test prior to starting treatment; males or females of reproductive 
potential may not participate unless they have agreed to use an effective contraceptive method during protocol therapy and for 
at least 30 days after the last dose of chemotherapy. Abstinence is an acceptable method of birth control. 
2 After Cycle 2, if positive at diagnosis. 
3 Echocardiogram prior to Cycle 4 and 6. 
4 If most recent PET was positive.  
5 All sites of disease should be evaluated after Cycle 2 and cycle 6. If not in CR or CRU after Cycle 2, obtain after Cycle 4  
6 MRD COLLECTED AT 3 TIMES POINTS: BASELINE PRIOR TO THERAPY, DAY 6 AT END OF PROPHASE 
BEFORE CYCLE 1 AND AT END OF CYCLE 1. PLEASE SEE SECTION 13 FOR DETAILS ON SPECIMEN 
SHIPPING. 
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain other studies as indicated for 
good clinical care.  


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
87 
 
7.2 
Follow-up  
The following studies are required until the patient is off study as defined in Section 8.2.  
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 
 
7.2.1 
Follow-up Table 
 
STUDIES TO BE 
OBTAINED 
Every 3 Months up 
to 12 Months  
(Months 3, 6,  
9, 12) 
Every 6 Months 
up to 24 Months  
(Months  
18, 24) 
Annually up to 
60 Months 
(Months 36,  
48, 60) 
History 
X 
X 
X 
Physical Exam with 
vital signs 
X 
X 
X 
CBC, differential, 
platelets1 
X 
X 
X 
Creatinine, ALT 
(SGPT), bilirubin1 
X 
X 
X 
Electrolytes 
including Ca++, PO4, 
Mg++2 
X 
X 
X 
Echocardiogram and 
EKG2 
X2 
 
 
CT or MRI (primary 
site and 
neck/chest/abd/pelvi
s)3 
X3 
X3 
 
Bone Scan (for bone 
primaries only)3 
X3 
X3 
 
1 Repeated as clinically indicated 
2 Obtain at month 12 
3  Disease evaluation should be at months 3, 6, 12, and 18 and as clinically indicated 
 
Obtain other studies as needed for good patient care and as per COG Late Effects 
Guidelines. 
 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/  
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
88 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) Progressive disease: The diagnosis of relapse or progression should be proven by biopsy 
and histology. 
b) Relapse: Relapse will be defined as a recurrence of disease at any site. The diagnosis of 
relapse or progression should be proven by biopsy and histology. 
c) Refusal of further protocol therapy by patient/parent/guardian. 
d) Completion of protocol therapy. 
e) Physician determines it is in patient’s best interest. 
f) Development of a second malignancy. 
g) Repeat eligibility studies (if required) are outside the parameters required for eligibility. 
h) Study is terminated by Sponsor. 
i) Pregnancy. 
j) Adverse Event requiring removal from protocol therapy (See Section 5.0). 
 
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 is withdrawn. 
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at 
recurrence). 
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 
Enrollment of newly diagnosed patients with ALCL to ANHL0131 averaged about 30 
patients per year. With the ANHL12P1 expanded eligibility criteria, namely stage II 
patients to be consistent with ALCL99, COG expects to enroll about 41 patients per year. 
As detailed below, enrollment up to 140 patients will be required (to enroll 128 eligible 
patients, evaluable for the primary adverse events outcome) and we expect that this 
enrollment will be accomplished in about 3.5 years.  
 
9.2 
Study Design 
This study is designed to evaluate the feasibility of the addition of brentuximab vedotin or 
crizotinib to standard chemotherapy (ALCL99). 
 
Patients will be randomized 1:1 to ALCL99 chemotherapy plus either brentuximab vedotin 
or crizotinib. Total enrollment will be up to 140 patients (70 per randomized treatment to 
assure the enrollment of 64 eligible patients on each of the 2 regimens. Should enrollment 
to one of the treatment regimens be closed (see below) prior to reaching 64 eligible patients, 
enrollment to the remaining regimen will continue to a total sample size that will assure 64 
eligible patients. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
89 
 
 
9.2.1 
Primary study endpoint:  
The primary study endpoints will be the occurrence of Grade 3+ non-hematologic 
adverse events and event-free survival defined as the time from study entry until 
progressive disease, relapse, or death. All patients receiving any protocol treatment 
will contribute to the primary analysis. 
 
Patient rates of certain Grade 3+ non-hematologic toxicities for each regimen (pre-
phase plus 6 cycles of alternating A/B courses) will be compared to those seen on 
ALCL99. Information about the ALCL99 adverse event experience is primarily 
available.30 The authors report patient level incidence rates for infection (21%); 
stomatitis (42%), and liver toxicity (defined as hyperbilirubinemia or AST/ALT 
elevation) (38%).  
 
For the first 10 patients of each arm, the study chair will review reported toxicities 
on a weekly basis through the COG system. The study committee will have 
conference calls at least every month reviewing all the adverse experience data, 
with focus on targeted toxicities. The study chair will review reported toxicities on 
a weekly basis and all deaths, and patients removed from study due to toxicity will 
be reported to the DSMC for review, as well. Because the patients will be 
monitored continuously by the study chair, the study committee, and the DSMC, 
the study will not be stopped after the first 10 patients of each arm to evaluate for 
toxicity. 
 
Because of concern regarding pulmonary toxicity with brentuximab vedotin and 
liver toxicity with crizotinib, these toxicities will be monitored. A 5% rate of Grade 
3+ pulmonary toxicity with brentuximab vedotin and a 5% rate of Grade 4+ liver 
toxicity with crizotinib are considered acceptable, but a true rate of 15% for either 
of these would be unacceptable. Thus interim analysis of these rates will be 
performed using an alpha-spending function approach using an O’Brien-Fleming 
monitoring boundary (truncated at 3 standard deviations) beginning at about 33% 
of the expected information (21 patients per treatment). 
 
With 64 eligible subjects, if only one analysis were to be done once all patients 
had completed treatment, the rule applied would be to declare the adverse event 
experience acceptable if six (6) or fewer patients experienced the targeted grade 
3+ or grade 4+ adverse event and unacceptable if seven (7) or more experienced 
this adverse event. Using exact binomial probabilities, the probability of declaring 
the adverse event rate unacceptable when the true rate is 5% is 4% (0.0403), 
whereas the probability of declaring the adverse event rate unacceptable when the 
true rate is 15% is 86% (0.8635). 
 
However, these rates of adverse event will be monitored during the conduct of the 
study. The actual rules for declaring the adverse event rate unacceptable will 
depend on when the monitoring takes place. The table below presents the 
boundaries should the interim monitoring be done at exactly 33%, 56%, 77% and 
100% of the expected information with the overall alpha expended equal to or less 
than 0.05. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
90 
 
Percent of total 
information 
Sample size 
for regimen 
Rule to reject adverse 
event rate of 5% 
Nominal alpha 
for comparison 
33% 
21 
6+ with adverse event 
0.00044 
56% 
36 
6+ with adverse event 
0.00834 
77% 
49 
7+ with adverse event 
0.01058 
100% 
64 
7+ with adverse event 
0.04030 
 
Total alpha is less than 0.05 because the individual tests to be performed are with 
the exact binomial distribution and these rules generate nominal alphas less than 
the O’Brien-Fleming boundary which produces an overall alpha of 0.05. 
Application of a similar rule (an alpha-spending function approach using an 
O’Brien-Fleming monitoring boundary truncated at 3 standard deviations 
beginning at about 33% of the expected information with subsequent interim 
looks) will have the same property. 
 
ALCL99 had 4 treatment related deaths (1%) during treatment. Therefore, we will 
suspend enrollment to any arm of the study if more than 1 patient dies to review 
the circumstances of the deaths. A recommendation to re-open enrollment might 
be made if causes other than therapy were thought to be the primary cause of death 
 
Due to the apparent increased risk of thromboembolic events and the requirement 
for prophylactic anticoagulation in Arm CZ, as of Amendment 6A additional 
stopping rules have been added. The trial will be stopped if any of the following 
occur in patients enrolled after Amendment 6A: 
 
• 
Two CVL-associated thrombotic events  
• 
Any one event of  
o Thromboembolic event  requiring surgical intervention, or  
o Pulmonary embolism 
• 
Two bleeding events, defined as Grade 2 or higher hemorrhage events as 
classified in CTCAE. Grade 2 or higher events correspond to bleeding 
events which require intervention and consist of major bleeding and 
clinically relevant minor bleeding. Please see Section 11.10 for reporting 
details. 
 
Evidence of improvement in event-free survival outcome compared to that 
expected outcome with ALCL99 therapy: There is anecdotal evidence that these 
agents are effective in CD30+/ALK+ disease. Long-term event-free survival (EFS) 
for ANHL12P1 patients is expected to be 70%. We will compare the EFS outcome 
for each regimen to a fixed exponential cure model with a “cure” rate of 70%, and 
the 30% who fail failing as exponential with lambda equal to 1.5 (95% of failures 
occurring in the first 2 years). Testing at a 10% level of statistical significance (1-
sided), there will be 90% power to detect an increase in long-term EFS from 70% 
to 84% (relative risk: 0.50:1.00). The EFS for each of the treatment regimens will 
be compared to the fixed standard using a 1-sample log-rank test. No formal 
comparison of EFS between the two randomized treatments is planned. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
91 
 
Futility monitoring plan 
The alternative hypothesis is that, compared with standard therapy, the risk of an 
event will be reduced by 50%; that is, the event-free survival (EFS) under the 
alternative is expected to be:  
1/2
exp(
( )
[0
1.
.7
0.3
5 )]
S
t
t

=
−
+
  
Let K be the number of failures observed in the available follow-up and R be the 
sum of the cumulative hazards associated with S(t) to time ti, where ti is the follow-
up for patient i. Then, under the alternative, T = K–R is approximately normal and 
may be used for interim monitoring. Under the alternative hypothesis, we expect 
to observe a total of about 10 failures among the 64 eligible patients randomized 
to each treatment. Formal interim monitoring for futility will be done twice for 
each regimen (at about 5 and 10 observed events). Should the test comparing the 
event-free survival outcome to S(t) have an associated 1-sided p-value less than 
0.05 for either treatment group at either interim analysis (indicating poorer EFS), 
the Data and Safety Monitoring Committee may consider suspending enrollment, 
because the observed outcome is inconsistent with the expected improvement in 
EFS with the addition of crizotinib or brentuximab vedotin to standard treatment. 
 
In the event that enrollment of one regimen is suspended (because of unacceptable 
toxicity or because EFS appears worse that that seen with ALCL99 therapy, 
enrollment of patients will continue and patients will be non-randomly assigned to 
the other treatment regimen.  
 
Because 95% of failures are expected to be observed in the first two years of 
follow-up, the minimal required follow-up for the EFS analyses will be 2 years 
from the enrollment of the last patient. 
 
9.2.2 
Secondary study endpoints:  
Prognostic significance of minimal residual disease (MRD): MRD evaluations will 
be performed at 3 time points (diagnosis, end of prophase (Day 6), and end of 
Cycle 1 (first Course A). Data from Damm-Welk et al. suggests that about half of 
the patients with ALK-positive ALCL will have tumor cells detected at diagnosis 
by PCR in bone marrow or peripheral blood, and that the failure rate for those with 
tumor cells detected by PCR in bone marrow or peripheral blood is much higher 
than that for patients who are PCR negative.29 For instance, 3 of 25 patients whose 
peripheral blood was negative for NPM-ALK by PCR at diagnosis relapsed (5-
year event-free survival: 80%) versus 10 of 27 patients whose peripheral blood 
was positive for NPM-ALK by PCR at diagnosis (5-year event-free survival: 
46%). The expected long-term event-free survival for all patients receiving 
ALCL99 therapy is 70%. Assuming a total sample size of 128 eligible patients and 
an equal number of patients with and without peripheral blood MRD at diagnosis, 
if 25 events is assumed to be the total expected information (allowing for the 
possibility that the ANHL12P1 EFS outcome may be improved), then there will 
be 80% power (testing at the 5% level of statistical significance, 1-sided) to detect 
a relative risk of 2.7:1.0 (corresponding approximately to an event-free survival of 
82% for MRD negative and 58% for MRD positive patients) consistent with the 
results of Damm-Welk et al. These comparisons will be made using the log-rank 
test. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
92 
 
9.3 
Methods of Analysis 
All patients will be included in the analyses provided they are eligible and evaluable for 
the particular endpoint (EFS, toxicity, etc.). The EFS for each of the treatment regimens 
will be compared to the fixed standard using Woolson’s 1-sample log-rank test.31 No 
formal comparison of EFS between the two randomized treatments is planned. MRD 
evaluations will be performed at 3 time points (diagnosis, end of prophase (Day 6), and 
end of Cycle 1) and groups analyzed using the log-rank test. Toxicities will be summarized 
by individual toxicity counts and incidence rate separated by arm and course. 
 
9.4 
Evaluability for Toxicity  
All patients will be evaluable for toxicity and included in the toxicity tables and summaries. 
 
9.5 
Gender and Minority Accrual Estimates  
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 
7 
13 
20 
Not Hispanic or Latino 
47 
73 
120 
Ethnic Category: Total of all subjects 
54 
86 
140* 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
5 
4 
10 
Black or African American 
7 
16 
23 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
42 
66 
107 
Racial Category: Total of all subjects 
54 
86 
140* 
* These totals must agree 
This distribution was derived from ANHL0131, A Phase III Trial of Treatment of Advanced-Stage 
Anaplastic Large Cell Lymphoma (ALCL) with Standard APO (Doxorubicin, Prednisone, 
Vincristine) versus Consolidation with a Regimen Including Vinblastine 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
93 
 
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). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE 
v4.0 as referenced on the CTEP website (i.e., v4.02 and all subsequent iterations prior to 
version 5.0). 
 
10.2 
Response Criteria Overview 
Response will be evaluated in this study using guidelines and response criteria that have 
been revised from previous protocols (ANHL0131 and ALCL99) and the recent work of 
the International Lymphoma Working Group’s revised recommendations for malignant 
lymphoma. 
 
Establishing strict response criteria for ALCL is complicated by the fact that a large number 
of patients possess extranodal disease which by its nature is more difficult to measure. In 
addition, establishing strict CT size criteria for presumptive lymphomatous nodal 
enlargement is complicated by a number of factors, including substantial size overlap 
between benign reactive lymphoid hyperplasia and malignant lymphadenopathy, 
interobserver measurement variability, obliquity of node orientation to the scan plane, 
multiplicity of criteria for size measurement (volumetric vs. bidimensional vs. 
unidimensional; short axis vs. long axis), variability of normal nodal size with body region 
and age. For children and younger adolescents, there are no established size limits for 
normal lymph nodes. Furthermore, in children reactive hyperplasia is common in the 
cervical, axillary, mesenteric, and inguinal regions, and may be associated with nodes up 
to 1.5-2 cm in diameter. In other anatomic regions, including the supraclavicular, 
retroperitoneal, iliac, mediastinal, and hilar regions, normal nodes are typically less than 1-
1.5 cm. Despite these limitations, certain features suggest lymphomatous involvement, 
such as contiguous nodal clustering or matting, and nodal FDG avidity.  
 
With these caveats in mind, the nodal size criterion used by previous lymphoma protocols 
will be used. For visceral organs (such as liver, spleen, kidney, lung) any focal mass lesion 
large enough to characterize is considered due to lymphomatous involvement unless the 
imaging characteristics indicate an alternative nature (e.g., cyst, hemangioma, abscess, 
etc.). Lesions too small to characterize are considered indeterminate unless follow-up 
studies allow characterization or tissue sampling is performed.  
 
A measurable lesion by CT or MRI is a lesion that can be accurately measured in 2 
orthogonal dimensions. For extranodal sites, this typically involves lesions of at least 1 cm 
diameter. Lymph nodes are considered abnormal if the long axis is  1.5 cm, regardless of 
the short axis. Lymph nodes with a long axis measuring between 1.1-1.5 cm are only 
considered abnormal if their short axis is  1.0 cm.  
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
94 
 
All measurable lesions should be measured in the axial plane on CT. All measurable 
lesions, representative of all involved organs, will be measured as target lesions at baseline 
and followed for response. Target lesions will be selected on the basis of size (i.e., largest 
lesions) and suitability for accurate repeated measurements by imaging or clinical exam. 
Lesions will be recorded with size expressed as the PPD (product of perpendicular 
diameters). The PPD is obtained by multiplying the longest diameter of the lesion by the 
maximal diameter perpendicular to the longest diameter in axial plane, and serves as a 
surrogate measurement of tumor volume, assuming the mass has a spherical or ellipsoid 
shape. The SPPD, or sum of the products of the perpendicular diameters, is obtained by 
adding the products of the perpendicular diameters of measured lesions. FDG-PET imaging 
will be performed as per clinical routine, adhering to the imaging guidelines. 
 
Non-measurable assessable lesions include permeative bone lesions, malignant ascites, 
malignant pleural/pericardial effusions, pulmonary or cutaneous lymphangitic spread, and 
lesions too small to accurately measure in 2 dimensions by CT. All non-target and non-
measurable assessable lesions should be recorded at baseline and noted on follow-up. 
 
10.3 
Response Criteria for Patients with ALCL 
 
10.3.1 Complete Response (CR) 
Disappearance of all evidence of disease from all sites. This will be determined by 
physical exam and imaging. All lymph nodes and nodal masses must have 
regressed on CT to normal size (< 1.5 cm in their greatest transverse diameter for 
nodes > 1.5 cm before therapy). Bone marrow aspirate/biopsy must be normal if 
initially positive and any macroscopic nodules in any organs detectable on imaging 
techniques should no longer be present. PET scans must be negative if initially 
positive.  
 
10.3.2 Complete Response Unconfirmed (CRu) 
A residual lymph node mass > 1.5 cm in greatest transverse diameter that has 
regressed by > 75% in sum of the products of the greatest perpendicular diameters 
(SPPD) or returned to normal size (< 1.5 cm in greatest diameter) will be 
considered CRu. Any residual lesions in organs that have decreased by >75% and 
with a negative PET scan will be considered CRu. When disease affects the liver, 
spleen or kidneys it may be the case that residual abnormalities are seen following 
treatment. These generally measure < 1 cm diameter. Patients with only residual 
positive bone lesions on PET and/or bone scans will be considered in CRu. Patients 
with bone involvement may have positive lesions on PET or bone scan for some 
time; therefore, these patients will be considered in CRu if the other residual 
lesions have disappeared, or if the residual lymph node mass or masses > 1.5 cm 
in greatest transverse diameter have regressed by > 75% in sum of the products of 
the greatest perpendicular diameters (SPPD).  
 
10.3.3 Partial Response (PR) 
≥ 50% decrease in the SPPD of the lesions. No new lesions. 
 
10.3.4 No Response (Stable Disease) 
Failure to qualify for a PR. No new lesions. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
95 
 
10.3.5 Progressive disease (PD) 
≥ 25% increase in the size of any lesions or appearance of new lesions. 
 
Caveat: The presence of a residual mass should not be considered as a failure in 
the majority of the cases if it is less than 25-30% of the initial tumor volume and 
should not imply any modifications of the treatment. In the ALCL99 series, many 
patients had a residual mass at the end of the treatment and were followed without 
evidence of progression 
 
10.3.6 Duration of Response 
 
10.3.6.1 Duration of overall response: The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started).The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented. 
 
10.3.6.2 Duration of stable disease: Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
96 
 
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 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the Grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 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.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Application (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label*.  
 
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial*. 
 
*In this study both brentuximab vedotin and crizotinib are considered investigational 
agents and should have adverse events reported as investigational agents. 
 
When a study includes both investigational and commercial agents, these rules apply: 
• 
Concurrent administration: When an investigational agent is used in combination with 
a commercial agent, the combination is considered to be investigational and expedited 
reporting of adverse events would follow the guidelines for investigational agents. 
• 
Sequential administration: When a study includes an investigational agent and a 
commercial agent on the same study arm, but the commercial agent is given for a 
period of time prior to starting the investigational agent, expedited reporting of adverse 
events which occur prior to starting the investigational agent would follow the 
guidelines for commercial agents. Once therapy with the investigational agent is 
initiated, all expedited reporting of adverse events follow the investigational agent 
reporting guidelines. 
 
11.3 
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 tables 
assigned to the protocol, using the CTEP Adverse Event 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: 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
97 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations 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. 
 
11.4 
Special Situations for Expedited Reporting  
11.4.1 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 tables in this protocol.  
 
11.4.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption 
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 to be serious AEs 
 
11.4.3 Death 
Reportable Categories of Death 
• 
Death attributable to a CTCAE term.  
• 
Death Neonatal: A disorder characterized by cessation of life during the first 
28 days of life.  
• 
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.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
• 
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.  


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
98 
 
 
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. 
 
11.4.4 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:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
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. 
 
11.4.5 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. 
 
11.4.6 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. 
 
11.4.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which 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. 
 
There is a possibility that the sperm of male patients treated on studies 
involving possible teratogenic agents may have been damaged. For this 
reason, pregnancy in partners of men on study needs be reported 
and followed in the same manner as a patient pregnancy. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
99 
 
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. 
 
11.4.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.”  Any 
Pregnancy loss should be 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. 
 
11.4.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring 
during the first 28 days after 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 
a neonatal death resulting from a patient pregnancy or pregnancy in 
partners of men on study as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
11.5 
Reporting Requirements for Specialized AEs 
11.5.1 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 (e.g., 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. 
 
11.5.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles.  
 
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent cycle. 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 cycle. 
 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
100 
 
11.5.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle of therapy and then 
reoccurs in a later cycle. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.6 
Exceptions to Expedited Reporting 
11.6.1 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. 
 
11.6.2 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 A for this protocol. 
 
11.7 
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. 
 
11.8 
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 web site 
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. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
101 
 
 
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. 
 
• 
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.  
• 
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 administration.  
• 
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.  
• 
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 required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to brentuximab vedotin and critzotinib 
to: 301-230-0159 (back-up: 301-897-7404).  
 
Also: Fax supporting documentation for AEs related to brentuximab vedotin AND 
crizotinib 
to 
COG 
for 
all 
IND 
studies 
(fax 
# 
310-640-9193 
attention: 
COGAERS@childrensoncologygroup.org; Attention: COG AERS Coordinator).  
• 
ALWAYS include the ticket number on all faxed documents. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
102 
 
11.9 
Reporting Table for Phase 1 and Early Phase 2 Studies 
Table A: Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (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) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 
CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above applies after this 
reporting period. 
Effective Date:May 5, 2011 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
103 
 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
Additional Reporting Instructions 
• 
Targeted toxicities such as pulmonary toxicity with brentuximab vedotin and 
liver toxicity with crizotinib will be monitored closely on this study. 
• 
Grade 2 or higher thromboembolic events require expedited reporting. All 
catheter-related thrombosis should be reported as thromboembolic events and 
not vascular access complications. This should be done for consistency to ensure 
that all events are graded similarly. 
• 
Grade 2 or higher hemorrhage (bleeding) events require expedited reporting. 
Please note that CTCAE uses the location of the hemorrhage to define the event 
(e.g. gastric hemorrhage, colonic hemorrhage, oral hemorrhage, etc.). 
 
Reporting Exceptions 
• 
Grades 1-4 
myelosuppression 
(anemia, 
neutropenia, 
thrombocytopenia; 
lymphopenia) do not require expedited reporting.  
• 
Grades 1-2 AST/ALT elevations do not require expedited reporting, and Grade 3 
AST/ALT elevations do not require expedited reporting if they recover 
to ≤ Grade 1 ( < 2.5 X ULN) or baseline within 7 days of study drug interruption. 
• 
Grade 3 febrile neutropenia does not require expedited reporting. 
• 
Grade 3 infection does not require expedited reporting. 
• 
Grade 3 nausea and vomiting of < 3 days duration does not require expedited 
reporting 
• 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia 
responsive to oral supplementation does not require expedited reporting. 
 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated 
pathway 
 
The following are expedited reporting requirements for adverse events experienced by 
patients on study who have not received any doses of an investigational agent on this study. 
 
Commercial reporting requirements are provided in Table B.  
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning 
of the event. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
104 
 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. CTEP-AERS 
Reporting Requirements for Adverse Events That Occur During Therapy with a 
Commercial Agent or Within 30 Days1 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, Probable, Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent, regardless of attribution. Any death that occurs more than 30 days after the last 
dose of treatment with a commercial agent which can be attributed (possibly, probably, 
or definitely) to the agent and is not due to cancer recurrence must be reported via 
CTEP-AERS. 
 
 
11.12 Routine Adverse Event Reporting 
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 toxicities 
reported via CTEP-AERS and all Grade 3 and higher Adverse Events (except what is listed 
in Section 11.10), and all Grade 1-2 Adverse Events which result in dose modifications 
(See Section 5.0).  
 
 
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 Safety and 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 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
105 
 
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. 
 
As explained earlier in Section 9.2, for the first 10 patients of each arm, the study chair will 
review reported toxicities on a weekly basis through the COG system. The study committee 
will have conference calls at least every month reviewing all the adverse event data, with 
focus on targeted toxicities. The study chair will review reported toxicities, all deaths, and 
patients removed from study for due to toxicity on weekly basis and will be reported to the 
DSMC for review, as well.  
 
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 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. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
106 
 
 
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 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. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
107 
 
13.0 
PATHOLOGY GUIDELINES AND SPECIAL STUDIES 
13.1 
Pathology Guidelines  
 
13.1.1 Pathology Goals 
1. Provide accurate diagnosis and classification of pediatric anaplastic large 
cell lymphoma included in this treatment protocol. The diagnosis to be 
based on both morphological and immunophenotypic criteria. 
2. Employ the World Health Organization Lymphoma Classification to 
facilitate concordance in diagnosis. 
3. Evaluate pediatric ALCL included in this protocol for pathologic features 
that may impact prognosis. 
 
13.1.2 Requirements for Handling Tissue or Cytology Specimens at Primary Institutions 
Tissue should, whenever possible, be obtained fresh and delivered immediately to 
the Pathology laboratory for optimal handling and distribution (fixation, snap 
freezing, cytogenetics, etc.) 
 
Representative tissue sections should be submitted for fixation including one block 
with 10% Formalin and, if possible, a second block of tissue with a different 
fixative routinely used by the local pathologist. 
 
13.1.3 Immunophenotyping Recommendations for Primary Institutions 
For initial determination of cell lineage (T or null) the methodology and criteria 
for immunophenotypic analysis defined by the submitting institution will be 
accepted. Recognized methods include paraffin section, immunohistochemistry, 
frozen section immunohistochemistry, and cytospin immunocytochemistry. 
Recommended antibodies 
• 
Two anti-B antibodies (CD79A, and CD20) 
• 
Two anti-T antibodies (CD3 and CD43 or CD3 and CD45RO) 
• 
CD30 
• 
CD15 
• 
EMA 
• 
ALK-1 
• 
LMP-1 and/or EBER 
13.1.4 Morphology 
The following are recognized morphological variants of anaplastic large cell 
lymphoma 
• 
Common type 
• 
Small cell variant 
• 
Lymphohistiocytic variant 
• 
Giant cell variant 
• 
Mixed variant: association in the same lymph node biopsy specimen 
of features of more than one morphological variant (i.e. common type 
plus small cell variant, common type plus lymphohistiocytic, small 
cell variant plus lymphohistiocytic variant etc.) 
• 
Unclassifiable: because of small biopsy specimens or peculiar 
morphological features (i.e. sarcomatous features, signet cells etc.). 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
108 
 
13.1.5 Bone Marrow 
Because of frequent occult bone marrow involvement, immunohistochemical 
studies using anti-CD30 and anti-ALK antibodies should be performed even if the 
bone marrow appears to be uninvolved on conventional examination. Note that 
ALK1 antibody does not always give reliable staining on fixed and decalcified 
trephine bone marrow biopsy. 
 
13.1.6 Study Pathologists 
For any questions regarding the pathology protocol or assistance with 
immunophenotyping studies, contact the pathologists listed below. Difficult cases 
may also be reviewed in consultation prior to enrollment with one of the 
pathologists listed below. 
 
Megan S. Lim, MD, PhD 
Director of Hematopathology 
Room 514/515 
Stellar-Chance Laboratories 
422 Curie Boulevard 
Philadelphia, PA 19104 
Phone: (215) 898-2925 
E-mail: Megan.Lim@uphs.upenn.edu  
 
Robert E. Hutchison, MD 
SUNY Upstate Medical University 
Pathology 
750 East Adams Street 
Syracuse, NY  13210 
Phone: (315) 464-6771 
Fax: 
(315) 464-7322 
E-mail: hutchisb@upstate.edu 
 
Rodney Miles, M.D., Ph.D.  
University of Utah Health Sciences Center/ARUP Laboratories   
Hematopathology Mail G02-100  
500 Chipeta Way  
Salt Lake City, UT 84108  
Phone: (801) 584-5240  
Fax: 
(801) 584-5124  
E-mail: Rodney.Miles@path.utah.edu  
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
109 
 
13.2 
Specimens to Submit For Central Pathology Review  
 
13.2.1 List of Specimen Types 
Materials to be submitted for retrospective pathology review are not required but 
strongly encouraged. If possible, please submit the following materials to the COG 
Biopathology Center (BPC): 
 
1. Paraffin blocks from tumor biopsy at original diagnosis and relapse (if 
applicable). If blocks are unavailable submit 30 unstained from one 
representative block and 2 H&E slides from each available block. For surgical 
biopsy specimens 10% buffered formalin is the preferred fixative. Please submit 
unbaked slides that air dried at room temperature for the unstained slides on silane 
coated slides (i.e. Fisher Superfrost Plus). 
 
2. One stained bone marrow aspirate smear (Romanowsky) and an H&E stained 
section and 6 unstained sections from the bone marrow clot and biopsy blocks.  
 
3. Representative peripheral blood smear (Romanowsky stain) containing 
lymphoma cells when peripheral blood involvement is suspected. 
 
4. All corresponding pathology and ancillary testing (i.e. flow cytometry, 
cytogenetics) reports should be submitted. 
 
5. COG Generic Specimen Transmittal Form along with the Pathology Data 
Collection Form (Institutional Pathology Form). 
 
13.2.2 Pathology Reports 
A copy of all pathology reports on each case must be submitted. These are required. 
This should include: 
 
• 
Final reports of diagnostic biopsies, bone marrow specimens, and cerebrospinal 
fluid specimens including all immunophenotyping reports of diagnostic biopsy, 
bone marrow specimens and cerebrospinal fluid specimens (if available) also 
include copies of flow cytometry histograms (if available); 
 
• 
Results of any genotypic studies (i.e. gene rearrangement or fluorescent in-situ 
hybridization studies); and 
 
• 
Results of any cytogenetic (karyotypic) analysis.  
 
13.2.3 Pathology Data Collection Forms (Institutional Pathology Form) 
A separate pathology data collection form (Institutional Pathology Form) must be 
completed and submitted along with the above materials. Also, indicate the 
primary institution pathology diagnosis utilizing the WHO32 on the data collection 
form.  
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
110 
 
13.2.4 Submission of Pathology Review Materials 
Label all review materials with the patient’s COG patient ID number and the surgical 
pathology identification number and block number from the corresponding pathology 
report. Send a completed COG Generic Specimen Transmittal Form with the 
pathology review materials by U.S. mail or using your institution’s courier account. 
All material submitted for central pathology review should be sent to: 
 
Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, WA 1340 
Columbus, OH  43205 
Phone: (614) 722-2894 
FAX: (614) 722-2897 
 
13.3 
Special Tissue Banking 
 
13.3.1 Tissue Banking 
If sufficient tissue is available, representative fresh tissue should be snap frozen 
for biology studies. It is recommended that a minimum of a 5x5x3 mm section of 
tumor tissue be placed in foil and snap frozen in the vapor phase of liquid nitrogen. 
Tissue should be stored at -70 to -80 degrees Centigrade until shipment. Label the 
foil with the patient’s BPC number and place the tissue in a zip lock bag labeled 
with the patient’s BPC number, specimen type and collection date. 
 
Specimen procurement kits for submission of frozen tumor tissue are provided 
upon request. To obtain a kit, click on the ‘Biopathology Center Application’ link 
on either the Protocol or the CRA Home Page of the COG web site. On the 
Biopathology Center Applications page, select the BPC Kit Management link to 
enter the Kit Management application. 
 
Ship the tissue on dry ice and include a transmittal form and the corresponding 
pathology report in the shipment. Specimens must be shipped Monday through 
Thursday for Tuesday through Friday delivery. Obtain a FedEx shipping label via 
the BPC Kit Management application.  
 
Ship to:  
Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, WA 1340 
Columbus, OH  43205 
Phone: (614) 722-2865 
FAX: (614) 722-2897 
 
13.4  
Peripheral Blood Studies for MDD/MRD (Required) 
MDD/MRD studies will be performed in children with ALCL. These correlative studies 
are required and the study chair must be notified if these samples are not available. 
RT-PCR will be performed on total RNA extracted from serial peripheral blood specimens, 
for detection of the t (2;5) NPM/ALK fusion transcript. Results will not be returned to the 
treating physician. 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
111 
 
Peripheral blood (15 mL) should be collected in EDTA (purple top) tubes. Use as many 
collection tubes as needed in order to collect the required volume. Record the exact time 
and date that the sample is drawn. Samples should be shipped room temperature, the same 
day as drawn. If the samples cannot be shipped immediately (i.e. is collected in the evening 
and will be shipped out the next morning via FedEx), they should be stored in a refrigerator 
until shipment. Note: Samples should be sent ASAP once drawn. 
 
Do not ship samples for delivery on a weekend or Holiday. Because Saturday/Sunday 
delivery is NOT available and the study requires fresh specimens, please collect MRD at 
appropriate times to allow for M-F delivery. There are 3 time points to collect blood. 
i. 
Baseline: Collect on weekdays for M-F delivery. 
ii. 
Day 6 (End of Prophase): Collect as close as possible to Day 6 for M-F delivery 
(if Day 6 is a Friday, please collect and send on Thursday for Friday delivery; 
if Day 6 is Saturday or Sunday collect on Sunday night or Monday am for 
Monday shipment). 
iii. 
End of Cycle 1: Collect as close as possible to end of Cycle 1 (prior to starting 
Cycle 2). Sample should be sent for M-F delivery. 
 
Each tube must be labeled with the patient’s study registration number, the study I.D., and 
the date and time the sample was drawn. Data should be recorded on the MDD/MRD 
specimen transmittal form, which must accompany the sample(s). Samples will be sent at 
room temperature. 
 
13.4.1 Shipment of Peripheral Blood  
• 
Label tube with patient’s registration number, the study ID (ANHL12P1) and 
date and time it was drawn. 
• 
Place tube(s) in water-tight envelope or container with absorbent material. 
• 
Place the container in a Styrofoam box. 
• 
Package sample as appropriate for biologic material. 
• 
Ship the sample on the same day it was obtained with FedEx priority 
overnight using the COG FedEx account number available at: 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf  
 
Ship to:  
Dr. Megan S. Lim 
Attention Dr. Delphine Rolland 
Room 514/515 
Stellar-Chance Laboratories 
422 Curie Boulevard 
Philadelphia, PA 19104 
Phone: (215) 898-2925 
E-mail: Megan.Lim@uphs.upenn.edu 
 
Email Dr. Megan Lim (Megan.Lim@uphs.upenn.edu) and Delphine Rolland 
(drolland@mail.med.upenn.edu) prior to Federal Express shipment of BM or 
PB samples. Do not ship samples for delivery on a weekend or Holiday. 
Samples should be sent ASAP once drawn. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
112 
 
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). 
 
CT and MRI guidelines are available on the COG Member site at: 
https://cogmembers.org/_files/reference/RefMaterial/DiagnosticImagingGuidelines_MRICT.pdf 
 
For PET scan guidelines please refer to the NCI guidelines for the recommended set of procedures 
for the acquisition and analysis of 18F-FDG PET scans of patients participating in NCI-sponsored 
diagnostic and therapeutic clinical trials, which can be found at the following link: 
https://imaging.cancer.gov/programs_resources/reports_publications/publications/clinical_trials_
guidelines.htm  
 
 
15.0 
SURGICAL GUIDELINES 
15.1 
Role of the Surgeon 
The role of the surgeon in patients with anaplastic large cell lymphoma (ALCL) is to obtain 
tissue for diagnosis and occasionally to treat complications related to the disease. In all 
cases, ALCL is considered a “systemic” disease and thus therapy revolves around 
chemotherapy rather than methods to achieve local control such as surgery or radiotherapy. 
For all sites, tissue should be sent to the pathologist FRESH for histopathology, 
immunohistochemistry, and cytogenetics. 
 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
113 
 
APPENDIX I: STAGING 
Stage 
Criteria for extent of disease 
I 
A single tumour (extranodal) or single anatomic area (nodal) with the exclusion of mediastinum 
or abdomen 
II 
A single tumor (extranodal) with regional node involvement 
Two or more nodal areas on the same side of the diaphragm 
Two single (extranodal) tumors with or without regional node involvement on the same side of 
the diaphragm 
A primary gastointestinal tumor usually in the ileocaeacal area with or without involvement of 
associated mesenteric nodes only, grossly completely resected 
III  
Two single tumors (extranodal) on opposite sides of the diaphragm 
Two or more nodal areas above and below the diaphragm 
All primary intra-thoracic tumours (mediastinal, pleural, thymic) 
All extensive primary intra-abdominal disease 
All paraspinal or epidural tumours regardless of other tumor site(s) 
IV 
Any of the above with initial CNS and/or bone marrow involvement 
 
Skin involvement 
Skin involvement should always be confirmed by biopsy. Skin infiltration by continuous tumor growth 
arising by extension from a contiguous lymph node or soft tissue tumor is not considered as primary skin 
involvement. 
 
Mediastinal involvement 
Mediastinal involvement should be confirmed by X-ray or CT-scan. If the histopathological diagnosis can 
be performed by biopsy of other organs such as peripheral lymph nodes, a biopsy is not necessary for 
obvious lesions that may jeopardize the patient. 
 
Lung involvement 
Lung involvement should be confirmed by X-ray or CT-scan. If the histopathological diagnosis can be 
performed by biopsy of other organs such as peripheral lymph nodes, a lung biopsy not necessary for 
obvious lesions that may jeopardize the patient  
 
Bone Marrow 
The presence of any lymphoma cells in a bone marrow aspirate or biopsy represents involvement of the 
marrow by lymphoma. Use of CD30 and/or ALK immunostaining is suggested as it is very helpful in 
demonstrating bone marrow involvement as involvement is often morphologically subtle. 
 
CNS involvement is considered if: 
1. 
Tumor cells are present in CNS or 
2. 
Cranial nerve palsy is present unexplained by a local extracerebral lesion or 
3. 
Cerebral or spinal tumor is diagnosed by CT or MRI 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
114 
 
APPENDIX II: PERFORMANCE STATUS CRITERIA 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
 
ECOG(Zubrod) 
Karnofsky 
Patients 17 and older 
Lansky* 
Patients age 1-16 
Score 
Description 
Score 
Description 
Score 
Description 
 
 
 
0 
 
 
Fully active, able to carry on 
all pre-disease performance 
without restriction. 
 
100 
Normal, no complaints, no 
evidence of disease. 
 
100 
 
Fully active, normal. 
 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease. 
 
90 
 
Minor restrictions in physically 
strenuous activity. 
 
 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of light or 
sedentary nature, e.g., light 
housework, office work. 
 
80 
Normal activity with effort, 
some signs or symptoms of 
disease. 
 
80 
 
Active, but tires more quickly. 
 
70 
Cares for self, unable to 
carry on normal activity or 
do active work. 
 
70 
Both greater restriction of and 
less time spent in play activity. 
 
 
 
 
2 
 
 
Ambulatory and capable of 
all self-care but unable to 
carry out any work 
activities. Up and about 
more than 50% of waking 
hours. 
 
60 
Required occasional 
assistance and frequent 
medical care. 
 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
 
 
50 
 
Requires considerable 
assistance and frequent 
medical care. 
 
 
50 
Gets dressed, but lies around 
much of the day; no active play, 
able to participate in all quiet 
play and activities. 
 
 
3 
 
Capable of only limited self-
care, confined to bed or 
chair more than 50% of 
waking hours. 
 
40 
Disabled, requires special 
care and assistance. 
 
40 
Mostly in bed; participates in 
quiet activities. 
 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
 
30 
In bed; needs assistance even 
for quiet play. 
 
 
4 
 
Completely disabled. 
Cannot carry on any self-
care. Totally confined to bed 
or chair. 
 
20 
Very sick, hospitalization 
indicated. Death not 
imminent. 
 
20 
Often sleeping; play entirely 
limited to very passive 
activities. 
 
10 
Moribund, fatal processes 
progressing rapidly. 
 
10 
 
No play; does not get out of 
bed. 
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
115 
 
APPENDIX III: CTEP 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. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity 
and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) 
must complete their annual registration using CTEP’s web-based Registration and Credential Repository 
(RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation requirements per registration type are outlined in 
the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list all 
clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
116 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements for ANHL12P1 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted ) 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and 
tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory Office 
immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on 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 
 
Note: The status given only reflects compliance with IRB documentation and institutional compliance 
with protocol-specific requirements as outlined by the Lead Network. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical data management 
system. Access to the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles assigned in Regulatory Support System (RSS). To access Rave via iMedidata, the site 
user must have an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam) and the appropriate 
Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) on either the LPO or 
participating organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
117 
 
the user must hold a minimum of an AP registration type. To hold the Rave Site Investigator role, the 
individual must be registered as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study 
has a DTL, individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on 
the DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the 
appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name 
and password, and click on the “accept” link in the upper right-corner of the iMedidata page. Please note, 
site users will not be able to access the study in Rave until all required Medidata and study specific trainings 
are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site registration 
approval for the study in RSS will also receive a separate invitation from iMedidata to activate their account. 
Account activation instructions are located on the CTSU website, Rave tab under the Rave resource 
materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ 
or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
118 
 
APPENDIX IV: COMMON SUBSTRATES, INHIBITORS AND INDUCERS OF CYP3A4 
This is not an inclusive list. Because the lists of these agents are constantly changing, it is important to 
regularly consult frequently-updated medical references. 
 
CYP3A4 substrates  
Strong 
Inhibitors1 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Inducers 
alfentanil4,5  
amiodarone4 
aprepitant5 
atorvastatin5 
benzodiazepines 
bortezomib 
brentuximab 
budesonide5 
buspirone5 
calcium channel blockers 
cisapride 
citalopram/escitalopram  
conivaptan5 
glucocorticoids2 
crizotinib 
cyclosporine4 
cyclophosphamide  
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
ergotamine5 
eplerenone5 
erlotinib 
esomeprazole 
estrogens 
etoposide 
everolimus5 
felodipine5 
fentanyl4 
fosaprepitant5 
gefitinib 
haloperidol 
HIV antiretrovirals 
HMG Co-A inhibitors5 
ifosfamide 
imatinib 
indinavir5 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib  
mifepristone 
nilotinib 
verapamil 
alprazolam 
amiodarone  
amlodipine 
atorvastatin 
bicalutamide 
cilostazol 
cimetidine 
ciprofloxacin  
cyclosporine 
fosaprepitant 
fluvoxamine 
isoniazid 
nicardipine 
propofol 
quinidine 
ranolazine 
 
armodafinil 
barbiturates 
bosentan 
carbamazepine 
deferasirox 
echinacea 
efavirenz 
etravirine 
fosphenytoin 
glucocorticoids2 
modafinil 
nafcillin 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
primidone 
rifabutin 
rifampin 
rifapentin 
ritonavir 
St. John’s wort 
topiramate 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
119 
 
irinotecan  
itraconazole 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
modafinil 
montelukast 
nefazodone 
nilotinib 
nisoldipine5 
omeprazole 
ondansetron 
paclitaxel 
pazopanib 
quetiapine5 
quinidine4 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sunitinib 
tacrolimus4,5 
telaprevir 
tamoxifen 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, 
goldenseal) may inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2 Dexamethasone is considered a weak CYP3A4 inducer. 
3 The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and 
is concentration-, dose-, and preparation-dependent. 
4 Narrow therapeutic range substrates 
5 Sensitive substrates 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
120 
 
APPENDIX V: CRIZOTINIB DOSING TABLES 
 
CRIZOTINIB: 165 mg/m2 PO BID dose level  
 
Dose Group 
Body Surface Area (m²) 
Dose 
A* 
 
250 mg PO once daily 
B 
0.9 – 1.29 
200 mg PO BID 
C 
1.3 – 1.44 
250 mg PO QAM and 
200 mg PO QPM 
D 
1.45 - ≥ 2.00 
250 mg PO BID 
* 
Dose Group A will only be utilized if Dose Group B needs dose modification to a lower dose level.  
All patients should be started using Dose Levels B, C, or D. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
121 
 
APPENDIX VI: POSSIBLE DRUG INTERACTIONS 
The lists below do not include everything that may interact with crizotinib and/or chemotherapy. Study 
patients and/or their parents should be encouraged to talk to their doctors before starting any new 
medications, using over-the-counter medicines, or herbal supplements and before making a 
significant change in the diet. 
 
Brentuixmab Vedotin: 
Drugs that may interact with brentuximab vedotin 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antifungals  
o Itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
• Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir 
• 
Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Nicardipine, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Bosentan, deferasirox, dexamethasone, lomitapide, natalizumab, nefazodone 
 
Food and supplements that may interact with brentuximab vedotin* 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
122 
 
Crizotinib: 
Drugs that may interact with crizotinib 
• Antibiotics  
o Ciprofloxacin, levofloxacin, moxifloxacin, clarithromycin, erythromycin, nafcillin, rifabutin, 
rifampin, telithromycin 
• Antidepressants and antipsychotics  
o Aripiprazole, buproprion, citalopram, clozapine, escitalopram, fluvoxamine, lurasidone, 
nefazodone, quetiapine 
• Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tofacitinib 
• 
Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
• Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, rilpivirine, ritonavir, saquinavir, Stribild, 
telaprevir, tipranavir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, amlodipine, dronedenarone, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Aprepitant, artemether/lumefantine, deferasirox, ivacaftor, lomitapide, mifepristone, 
natalizumab, nimodipine, praziquantel, warfarin  
Food and supplements* that may interact with crizotinib 
• 
Echinacea 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
123 
 
Cyclophosphamide: 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
Cytarabine: 
Drugs that may interact with cytarabine 
• Clozapine 
• Digoxin  
• Flucytosine 
• Leflunomide 
 
Food and supplements that may interact with cytarabine* 
• Echinacea 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
 
Drugs that may interact with cyclophosphamide 
• 
Allopurinol 
• 
Chloramphenicol 
• 
Cyclosporine 
• 
Digoxin  
• 
Etanercept  
• 
Hydrochlorothiazide 
• 
Indomethacin 
• 
Nevirapine 
• 
Ondansetron 
• 
Pentostatin  
• 
Tamoxifen 
• 
Trastuzumab  
• 
Warfarin 
Food and supplements that may interact with cyclophosphamide* 
• 
St John’s Wort 
• 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
124 
 
Dexamethasone (Decadron): 
Drugs that may interact with dexamethasone 
• Antibiotics  
o Ciprofloxacin, levofloxacin, moxifloxacin, clarithromycin, erythromycin, nafcillin, rifabutin, 
rifampin, telithromycin 
• Antidepressants and antipsychotics  
o Aripiprazole, buproprion, citalopram, clozapine, escitalopram, fluvoxamine, lurasidone, 
nefazodone, quetiapine 
• Antifungals  
o Caspofungin, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
• Antiretrovirals and antivirals 
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, rilpivirine, ritonavir, saquinavir, Stribild, telaprevir, tipranavir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, amlodipine, dronedenarone, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Some oral contraceptives or birth control medications 
• Many other drugs, including the following: 
o Aprepitant, artemether/lumefantine, aspirin, deferasirox, ibuprofen, ivacaftor, lomitapide, 
mifepristone, natalizumab, nimodipine, praziquantel, warfarin 
 
Food and supplements that may interact with dexamethasone* 
• Echinacea 
• St John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Doxorubicin: 
Drugs that may interact with doxorubicin 
• Some antiepileptics (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, fosphenytoin) 
• Some antiretrovirals (stavudine, zidovudine) 
• Other agents, such as clozapine, cyclosporine, verapamil, and warfarin 
 
Food and supplements that may interact with doxorubicin* 
• Echinacea 
• Glucosamine  
• St. John’s Wort 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
125 
 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
• Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Etoposide: 
Drugs that may interact with etoposide 
• 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
o Aripiprazole, clozapine, nefazodone 
• 
Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• 
Arthritis medications  
o Leflunomide, tofacitinib 
• 
Anti-rejection medications 
o Cyclosporine, tacrolimus 
• 
Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, 
tipranavir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• 
Heart medications  
o Amiodarone, dronedenarone, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Aprepitant, atovaquone, bosentan, deferasirox, dexamethasone, ivacaftor, lomitapide, 
mifepristone, natalizumab, pimozide, sitaxentan 
 
Food and supplements that may interact with etoposide* 
• 
Echinacea 
• 
Glucosamine 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
126 
 
Hydrocortisone: 
Drugs that may interact with hydrocortisone 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Antiretrovirals and antivirals  
o Darunavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tenofovir, tipranivir 
• Anti-seizure medications  
o Carbamazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, carvedilol, dronedarone, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Some oral contraceptives or birth control medications 
• Many other drugs, including the following: 
o Aprepitant, aripiprazole, clarithromycin, cyclosporine, deferasirox, itraconazole, ivacaftor, 
ketoconazole, mifepristone, natalizumab, nefazodone, rifampin, tacrolimus, trazodone, warfarin 
 
Food and supplements that may interact with hydrocortisone* 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Ifosfamide: 
Drugs that may interact with ifosfamide 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
o Citalopram, clozapine, escitalopram, fluvoxamine, lurasidone, nefazodone, paliperidone, 
quetiapine, thioridizine, ziprasidone 
• Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Anti-rejection medications 
o Cyclosporine 
• Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, tipranavir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, dronedenarone, verapamil 
• Stomach and reflux medications 
o Esomeprazole, omeprazole 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
127 
 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Bosentan, sitaxentan, aprepitant, dexamethasone, lomitapide, mifepristone, natalizumab, 
pimozide  
 
Food and supplements that may interact with ifosfamide* 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Leucovorin: 
Drugs that may interact with leucovorin 
• Some antiepileptics (fosphenytoin, phenobarbital, phenytoin, primidone) 
 
Food and supplements that may interact with leucovorin* 
• Folic acid 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
Methotrexate (IV): 
Drugs that may interact with methotrexate 
• 
Some antibiotics (amoxicillin, Bactrim, chloramphenicol, ciprofloxacin, penicillin, piperacillin, 
tetracycline) 
• 
Some anti-inflammatory drugs (aspirin, acetaminophen, ibuprofen, naproxen, ketorolac) 
• 
Some heartburn medications (esomeprazole, lansoprazole, omeprazole, pantoprazole) 
• 
Several other specific agents, including the following: amiodarone, clozapine, cyclosporine, 
eltrombopag, leflunomide, phenytoin, pimecrolimus, probenecid, pyrimethamine, retinoids, 
theophylline, warfain 
 
Food and supplements that may interact with methotrexate* 
• 
Alcohol 
• 
Echinacea 
• 
Some vitamins, including those that contain folic acid or high doses of vitamin C 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided. 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
128 
 
APPENDIX VII: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ANHL12P1 
(for children from 7 through 12 years of age) 
 
 
1 
We have been talking with you about Anaplastic Large Cell Lymphoma (ALCL). ALCL is a type 
of cancer of the immune system. ALCL happens when a type of white blood cell that fights 
infection does not grow normally. After doing tests, we have found that you have this type of 
cancer. 
 
2 
We are asking you to take part in a research study because you have ALCL. A research study is 
when doctors work together to try out new ways to help people who are sick. In this study, we want 
to learn more about how to treat children with ALCL.  
 
3 
All children who are part of this study will get the standard treatment for ALCL. The standard 
treatment is with chemotherapy. Chemotherapy is medicine that kills cancer. In this study, one 
group of children will get an extra medicine called brentuximab vedotin and another group of 
children will get an extra medicine called crizotinib. The extra medicine you get will be decided by 
chance, like flipping a coin for “heads” or “tails.” Your doctor will tell you which group you are 
in. We do not know if treatment with either of the extra medicines will be better than usual 
treatment. That is why we are doing this study. 
 
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 getting rid of the 
cancer for as long as possible, and with fewer bad effects; 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. There is a risk that 
you will have more bad effects from adding either brentuximab vedotin or critzotnib to your usual 
medicines. We do not know this for sure which is why we are doing this study. 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 also going to collect extra blood three times during the study. We want to see if there are 
ways to tell how the cancer will respond to treatment. This sample would be taken when other 
regular blood tests are being performed. 
 
8 
We are also asking permission to save leftover tissue for future research to help us learn more about 
cancer and other diseases. This would be taken when a regular biopsy is being performed and will 
not involve an extra procedure. You can still take part in this study even if you don’t allow us to 
collect the extra tissue and/or save leftover samples for future research. 
  
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
129 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ANHL12P1 
(for teens from 13 through 17 years of age) 
 
 
1 
We have been talking with you about Anaplastic Large Cell Lymphoma (ALCL). ALCL is a type 
of cancer of the immune system. ALCL happens when a type of white blood cell that fights 
infection, called “lymphocytes” grows abnormally. After doing tests, we have found that you have 
this type of cancer. 
 
2 
We are asking you to take part in a research study because you have ALCL. A research study is 
when doctors work together to try out new ways to help people who are sick. In this study, we want 
to learn more about how to treat children and teens ALCL.  
 
3 
All children and teens who are part of this study will get the standard treatment for ALCL. The 
standard treatment is with chemotherapy. Chemotherapy is medicine that kills cancer. In this study, 
one group of children will get an extra medicine called brentuximab vedotin and another group of 
children will get an extra medicine called crizotinib. The extra medicine you get will be decided by 
chance, like flipping a coin for “heads” or “tails.” Your doctor will tell you which group you are 
in. We do not know if treatment with either of the extra medicines will be better than usual 
treatment. That is why we are doing this study. 
 
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 getting rid of the 
cancer for as long as possible, and with fewer bad effects; 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. There is a risk that 
you will have more bad effects from adding either brentuximab vedotin or crizotinib to your usual 
medicines. We do not know this for sure which is why we are doing this study. 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 also going to collect extra blood three times during the study. We want to see if there are 
ways to tell how the cancer will respond to treatment. This sample would be taken when other 
regular blood tests are being performed. 
 
8 
We are also asking permission to save leftover tissue for future research to help us learn more 
about cancer and other diseases. This would be taken when a regular biopsy is being performed 
and will not involve an extra procedure. You can still take part in this study even if you don’t 
allow us to collect the extra tissue and/or save leftover samples for future research. 
 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
130 
 
REFERENCES 
1. 
Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334:1238-
48, 1996 
2. 
Seidemann K, Tiemann M, Schrappe M, et al: Short-pulse B-non-Hodgkin lymphoma-type 
chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the 
Berlin-Frankfurt-Munster Group Trial NHL-BFM 90. Blood 97:3699-706, 2001 
3. 
Stein H, Mason DY, Gerdes J, et al: The expression of the Hodgkin's disease associated antigen Ki-1 in 
reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies 
are derived from activated lymphoid cells. Blood 66:848-58, 1985 
4. 
Brugieres L, Deley MC, Pacquement H, et al: CD30(+) anaplastic large-cell lymphoma in children: 
analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. 
Blood 92:3591-8, 1998 
5. 
Brugieres L, Le Deley MC, Rosolen A, et al: Impact of the methotrexate administration dose on the need 
for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a 
randomized trial of the EICNHL Group. J Clin Oncol 27:897-903, 2009 
6. 
Laver JH, Kraveka JM, Hutchison RE, et al: Advanced-stage large-cell lymphoma in children and 
adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose 
cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial. J 
Clin Oncol 23:541-7, 2005 
7. 
Lowe EJ, Sposto R, Perkins SL, et al: Intensive chemotherapy for systemic anaplastic large cell 
lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941. Pediatr 
Blood Cancer 52:335-9, 2009 
8. 
Rosolen A, Pillon M, Garaventa A, et al: Anaplastic large cell lymphoma treated with a leukemia-like 
therapy: report of the Italian Association of Pediatric Hematology and Oncology (AIEOP) LNH-92 
protocol. Cancer 104:2133-40, 2005 
9. 
Williams DM, Hobson R, Imeson J, et al: Anaplastic large cell lymphoma in childhood: analysis of 72 
patients treated on The United Kingdom Children's Cancer Study Group chemotherapy regimens. Br J 
Haematol 117:812-20, 2002 
10. 
Le Deley MC, Rosolen A, Williams DM, et al: Vinblastine in children and adolescents with high-risk 
anaplastic large-cell lymphoma: results of the randomized ALCL99-vinblastine trial. J Clin Oncol 
28:3987-93, 2010 
11. 
Woessmann W, Zimmermann M, Lenhard M, et al: Relapsed or refractory anaplastic large-cell 
lymphoma in children and adolescents after Berlin-Frankfurt-Muenster (BFM)-type first-line therapy: a 
BFM-group study. J Clin Oncol 29:3065-71, 2011 
12. 
Woessmann W, Peters C, Lenhard M, et al: Allogeneic haematopoietic stem cell transplantation in 
relapsed or refractory anaplastic large cell lymphoma of children and adolescents--a Berlin-Frankfurt-
Munster group report. Br J Haematol 133:176-82, 2006 
13. 
Stein H, Foss HD, Durkop H, et al: CD30(+) anaplastic large cell lymphoma: a review of its 
histopathologic, genetic, and clinical features. Blood 96:3681-95, 2000 
14. 
Alley S, Oflazoglu E, Jonas M, et al: Abstract #3234: Antibody-targeted delivery of auristatin using 
SGN-35 leads to one to two logs greater intratumoral auristatin concentrations than non-targeted therapy. 
AACR Meeting Abstracts 2009:3234-, 2009 
15. 
Fanale M, Bartlett NL, Forero-Torres A, et al: The Antibody-Drug Conjugate Brentuximab Vedotin 
(SGN-35) Induced Multiple Objective Responses in Patients with Relapsed or Refractory CD30-


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ANHL12P1 
Version Date: 02/01/2019 
131 
 
Positive Lymphomas in a Phase 1 Weekly Dosing Study. ASH Annual Meeting Abstracts 114:2731-, 
2009 
16. 
Younes A, Bartlett NL, Leonard JP, et al: Brentuximab vedotin (SGN-35) for relapsed CD30-positive 
lymphomas. N Engl J Med 363:1812-21, 2010 
17. 
Younes A, Forero-Torres A, Bartlett NL, et al: Multiple Complete Responses in a Phase 1 Dose-
Escalation Study of the Antibody-Drug Conjugate SGN-35 in Patients with Relapsed or Refractory 
CD30-Positive Lymphomas. ASH Annual Meeting Abstracts 112:1006-, 2008 
18. 
Advani RH, Shustov AR, Brice P, et al: Brentuximab Vedotin (SGN-35) in Patients with Relapsed or 
Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study Update. ASH Annual Meeting 
Abstracts 118:443-, 2011 
19. 
Chen R, Gopal AK, Smith SE, et al: Results of a Pivotal Phase 2 Study of Brentuximab Vedotin (SGN-
35) in Patients with Relapsed or Refractory Hodgkin Lymphoma. ASH Annual Meeting Abstracts 
116:283-, 2010 
20. 
Younes A, Connors JM, Park SI, et al: Frontline Therapy with Brentuximab Vedotin Combined with 
ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma. ASH Annual 
Meeting Abstracts 118:955-, 2011 
21. 
Perkins SL, Pickering D, Lowe EJ, et al: Childhood anaplastic large cell lymphoma has a high incidence 
of ALK gene rearrangement as determined by immunohistochemical staining and fluorescent in situ 
hybridisation: a genetic and pathological correlation. Br J Haematol 131:624-7, 2005 
22. 
Chiarle R, Voena C, Ambrogio C, et al: The anaplastic lymphoma kinase in the pathogenesis of cancer. 
Nat Rev Cancer 8:11-23, 2008 
23. 
Christensen JG, Zou HY, Arango ME, et al: Cytoreductive antitumor activity of PF-2341066, a novel 
inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell 
lymphoma. Mol Cancer Ther 6:3314-22, 2007 
24. 
Administration UFaD: FDA labeling information - Xalkori, 2011 
25. 
Gambacorti-Passerini C, Messa C, Pogliani EM: Crizotinib in anaplastic large-cell lymphoma. N Engl 
J Med 364:775-6, 2011 
26. 
Mosse YP, Balis FM, Lim MS, et al: Efficacy of crizotinib in children with relapsed/refractory ALK-
driven tumors including anaplastic large cell lymphoma and neuroblastoma: A Children's Oncology 
Group phase I consortium study. J Clin Oncol 30, 2012 
27. 
Attarbaschi A, Mann G, Rosolen A, et al: Limited stage I disease is not necessarily indicative of an 
excellent prognosis in childhood anaplastic large cell lymphoma. Blood 117:5616-9, 2011 
28. 
Le Deley MC, Reiter A, Williams D, et al: Prognostic factors in childhood anaplastic large cell 
lymphoma: results of a large European intergroup study. Blood 111:1560-6, 2008 
29. 
Damm-Welk C, Busch K, Burkhardt B, et al: Prognostic significance of circulating tumor cells in bone 
marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-
positive anaplastic large-cell lymphoma. Blood 110:670-7, 2007 
30. 
Wrobel G, Mauguen A, Rosolen A, et al: Safety assessment of intensive induction therapy in childhood 
anaplastic large cell lymphoma: report of the ALCL99 randomised trial. Pediatr Blood Cancer 56:1071-
7, 2011 
31. 
 Woolson RL: Rank Tests and a One-Sample Logrank Test for Comparing Observed Survival Data to a 
Standard Population. Biometrics 37:687-96, 1981 
32. 
 Swerdlow SH, Campo E, Harris NL, et al: WHO Classification of Tumours of Haematopoietic and 
Lymphoid Tissues (ed 4th). Lyon, IARC, 2008