Clinical trial NCT03792256
Conditions: Leukemia, Lymphocytic Lymphoblastic Lymphoma T-cell Lymphoma T-cell Leukemia Recurrent Disease Acute Leukemia
Sponsor: Children's Oncology Group
Start date: 2019-04-11; Completion date: 2023-09-30
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
AINV18P1 is a Phase 1 study where palbociclib will be administrated in combination with a standard re-induction platform in pediatric relapsed Acute Lymphoblastic Leukemia (ALL) and lymphoblastic lymphoma (LL). LL patients are included because the patient population is rare and these patients are most commonly treated with ALL regimens. The proposed palbociclib starting dose for this study will be 50 mg/m\^2/day for 21 days.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of palbociclib administered in combination with re-induction chemotherapy in pediatric patients with relapsed B- or T-lineage ALL/LL.

II. To define and describe the toxicities of palbociclib administered on this schedule.

III. To characterize the pharmacokinetics of palbociclib in pediatric patients with relapsed B- or T-lineage ALL/LL.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of palbociclib in combination with chemotherapy for children with relapsed ALL/LL within the confines of a Phase 1 study.

II. To assess the biologic activity of palbociclib in this patient population.

OUTLINE:

Patients receive Palbociclib PO (or via NG-tube) once daily on Days 1-21; Intrathecal cytarabine (IT ARAC) on Day 1, Doxorubicin IV push or infusion over 1-15 min on Day 4; Prednisone or prednisolone PO on days 4-31; Vincristine IV push or mini-bag per institutional policy on Days 4, 11, 18, and 25; and Pegaspargase IV over 1-2 hours on Days 5, and 18. If CNS3 leukemia is present, patients receive Intrathecal Triple Therapy (ITT) on days 4, 11,18, and 25. If CNS1 or 2 disease status, patients receive Methotrexate (IT MTX) on Days 18 and 32. Patients known to be CNS3 at study entry may receive ITT on Day 1 rather than IT ARAC. Treatment will be given for one cycle, 32 days, in the absence of disease progression or unacceptable toxicity.

Arms: arm 1: Patients receive Palbociclib 50 mg/m\^2 (starting dose with maximum dose of 100 mg) PO (or via NG-tube) once daily on Days 1-21; Intrathecal cytarabine (IT ARAC) age-based dosing on Day 1, Doxorubicin 60 mg/m\^2 IV push or infusion over 1-15 min on Day 4; Prednisone or prednisolone 40 mg/m\^2 PO divided BID or TID on days 4-31; Vincristine 1.5 mg/m\^2 (maximum dose 2 mg) IV push or mini-bag per institutional policy on days 4, 11, 18, and 25; and Pegaspargase 2500 IU/m\^2 IV over 1-2 hours on Days 5, and 18. If CNS3 leukemia is present, patients receive Intrathecal Triple Therapy (ITT) age-based dosing on days 4, 11, 18, and 25. Patients known to be CNS3 at study entry may receive ITT on Day 1 rather than IT ARAC. If CNS1 and 2 leukemia present, patient receive Methotrexate (IT MTX) age-based dosing on Days 18 and 32. Treatment will be given for one cycle, 32 days, in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Palbociclib intervention 2: Cytarabine intervention 3: Methotrexate intervention 4: Hydrocortisone intervention 5: Doxorubicin intervention 6: Prednisolone intervention 7: Vincristine intervention 8: Pegaspargase intervention 9: Hydrocortisone intervention 10: Prednisone
Intervention descriptions: intervention 1: Given PO (or via NG- tube) intervention 2: Given intrathecally (IT) intervention 3: Given intrathecally (IT) intervention 4: Given IT intervention 5: Given intravenously (IV) intervention 6: Either prednisone or prednisolone is given PO intervention 7: Given IV intervention 8: Given IV intervention 9: Given intrathecally (IT) intervention 10: Either prednisone or prednisolone is given PO

Protocol documents:
Prot_SAP_000.pdf: 
AINV18P1 
Version Date:   01/23/20   
Page 1 
Activated: 1/14/19 
Version Date: 01/23/20 
Closed:  
5/21/21 
Amendment #: 1 
CHILDREN’S ONCOLOGY GROUP 
AINV18P1 
A PHASE 1 STUDY OF PALBOCICLIB 
, A CDK 4/6 INHIBITOR, IN 
COMBINATION WITH CHEMOTHERAPY IN CHILDREN WITH RELAPSED ACUTE 
LYMPHOBLASTIC LEUKEMIA (ALL) OR LYMPHOBLASTIC LYMPHOMA (LL) 
Participation Limited to the 21 COG sites that constituted the Phase 1 Consortium and the 
following institutions: 
CA078: Loma Linda University Medical Center 
CA139: Lucile Packard Children's Hospital Stanford University 
MD017: Johns Hopkins University/Sidney Kimmel Cancer Center 
NC007: UNC Lineberger Comprehensive Cancer Center 
NY011: Laura and Isaac Perlmutter Cancer Center at NYU Langone 
OK003: University of Oklahoma Health Sciences Center 
TX020: Cook Children's Medical Center 
UT002: Primary Children's Hospital 
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. 
 
 
 
 
 
For COG Operations Contacts see: http://members.childrensoncologygroup.org 


 
 
AINV18P1 
 
                                                                                                                      
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TABLE OF CONTENTS 
SECTION 
PAGE 
 
CHILDREN’S ONCOLOGY GROUP 
1 
STUDY COMMITTEE 
5 
COG OPERATIONS STAFF 
6 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
 
Primary Aims 
8 
 
Secondary Aims 
8 
2.0 
BACKGROUND 
8 
 
Introduction/Rationale for Development 
8 
 
Preclinical Studies 
9 
 
Adult Studies 
14 
 
Pediatric Studies 
14 
 
Overview of Proposed Pediatric Study 
14 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
16 
 
Current Study Status 
16 
 
IRB Approval 
16 
 
Patient Registration 
16 
 
Reservation and Contact Requirements 
16 
 
Informed Consent/Assent 
16 
 
Screening Procedures 
16 
 
Eligibility Checklist 
17 
 
Institutional Pathology Report 
17 
 
Study Enrollment 
17 
 
Dose Assignment 
17 
4.0 
PATIENT ELIGIBILITY 
17 
 
Inclusion Criteria 
18 
 
Exclusion Criteria 
21 
5.0 
TREATMENT PROGRAM 
23 
 
Overview of Treatment Plan 
23 
 
Dosing Schema 
26 
 
Grading of Adverse Events 
26 
 
Definition of Dose-Limiting Toxicity (DLT) 
26 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
28 
 
Dose Modifications for Non-Hematological Toxicity Attributable to Palbociclib 
28 
 
Dose Modifications for Specific Toxicities Defined Per Drug 
28 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
35 
 
Concurrent Anticancer Therapy 
35 
 
Investigational Agents 
35 
 
Supportive Care 
35 
 
Growth Factors 
37 
 
Concomitant Medications 
37 


 
 
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
40 
 
Required Clinical, Laboratory and Disease Evaluation 
40 
 
Pharmacology (required) 
41 
 
Correlative Biology Studies (Optional) 
42 
9.0 
AGENT INFORMATION 
44 
 
Palbociclib 
44 
 
Cytarabine        (07/13/15) 
50 
 
Methotrexate        (05/07/19) 
51 
 
Intrathecal Triples      (05/08/12) 
53 
 
Doxorubicin        (05/09/11) 
55 
 
PREDNISO(LO)NE      (11/16/17) 
57 
 
Vincristine         (08/16/12) 
58 
 
Pegaspargase        (06/05/17) 
60 
 
Asparaginase Erwinia Chrysanthemi 
62 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
65 
 
Criteria for Removal from Protocol Therapy 
65 
 
Off Study Criteria 
65 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
66 
 
Sample Size and Study Duration 
66 
 
Definitions 
66 
 
Dose Confirmation and Determination of MTD 
67 
 
Inclusion of Children, Women and Minorities 
68 
 
Pharmacokinetic and Correlative Studies and Response Analysis 
68 
 
Study Design 
68 
 
Method of Analysis 
69 
12.0 
EVALUATION CRITERIA 
69 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
69 
 
Response Criteria for Patients with Relapsed Acute Lymphoblastic Leukemia 
69 
 
Central Nervous System (CNS) involvement of leukemia or lymphoma at relapse 
71 
 
Response Criteria for Patients with Relapsed Lymphoblastic Lymphoma 
71 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
75 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
76 
 
Reporting of Adverse Events for commercial agents – AINV18P1 abbreviated pathway 77 
 
When to Report an Event in an Expedited Manner 
79 
 
Expedited Reporting Methods 
79 
 
Definition of Onset and Resolution of Adverse Events 
80 
 
Other Recipients of Adverse Event Reports 
80 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
81 
 
Categories of Research Records 
81 
 
Data and Safety Monitoring Plan 
81 
REFERENCES 
83 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
85 
APPENDIX II: ASSESSING THE BIOLOGICAL ACTIVITY OF PALBOCICLIB: CORRELATIVE 
BIOLOGY STUDY SUMMARY 
86 
APPENDIX III:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
88 


 
 
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APPENDIX IV: ADDITIONAL INFORMATION FOR CORRELATIVE BIOLOGY STUDIES: 
DETERMINING THE BIOLOGICAL ACTIVITY OF PALBOCICLIB 
90 
APPENDIX V-A: Palbociclib Capsule Dosing Nomogram 
92 
APPENDIX V-B: PALBOCICLIB DOSING PREPARATION (LIQUID FORMULATION) 
93 
APPENDIX VI: 
THERAPY DELIVERY MAP (TDM) (PATIENTS WITH ALL) 
94 
APPENDIX VII: 
THERAPY DELIVERY MAP (TDM) (PATIENTS WITH LL) 
98 
APPENDIX VIII:  PHARMACOKINETIC STUDY FORM 
102 
APPENDIX IX:  CORRRELATIVE BONE MARROW AND PERIPHERAL BLOOD STUDIES FORM 
(ONLY FOR PATIENTS WITH ALL) 
103 
APPENDIX X: CORRELATIVES STUDIES GUIDE 
105 
APPENDIX XI: TOXICITY-SPECIFIC GRADING 
106 
APPENDIX XII: PATIENT DIARY FOR PALBOCICLIB 
107 
APPENDIX XIII: POSSIBLE DRUG INTERACTIONS 
110 
 


 
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AGENT NSC#72256 AND 
 
 
Palbociclib 
 
 
 
 
 
 
 
 
For COG Phase 1/Pilot Consortium Operations 
Contacts see: https://members.childrensoncologygroup.org 
IND Sponsor: COG 
 
SEE Section 8.2.6, AND Section 8.3.6  FOR SPECIMEN SHIPPING ADDRESSES 


 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects.  The Certificate protects 
against the involuntary release of information about subjects collected during the course of our covered 
studies.  The researchers involved in the studies cannot be forced to disclose the identity or any 
information collected in the study in any legal proceedings at the federal, state, or local level, regardless 
of whether they are criminal, administrative, or legislative proceedings.  However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain circumstances.  For 
example, if the subject or his/her guardian requests the release of information in writing, the Certificate 
does not protect against that voluntary disclosure.  Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program evaluation 
or an FDA request under the Food, Drug and Cosmetics Act. 
 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm 
to self or others. 
 
ABSTRACT 
 
AINV18P1 is a pilot study evaluating safety and feasibility of palbociclib in combination with an 
established re-induction platform for children, adolescents and young adults with relapsed/refractory ALL 
and lymphoblastic lymphoma. Targeting cell cycle progression has been an effective therapeutic strategy 
in a spectrum of malignancies.  Prior studies have shown that deregulation of the physiological cell cycle 
machinery is essential for both the induction and progression of ALL. Additionally, molecular targeting 
of the interaction of D type cyclins with cell cycle dependent kinases (CDK4 and 6) efficiently suppressed 
ALL growth and disease progression in vivo and this effect was augmented by concomitant delivery of 
cytotoxic agents.   
 
Palbociclib is an orally active, potent, selective inhibitor of CDK4 and CDK6.  CDK6 is highly 
homologous to CDK4 and can perform the same function by phosphorylating retinoblastoma protein 
(Rb), thus potentially creating a redundant mechanism to promote cell cycle progression.  Inhibition of 
both enzymes is therefore necessary to ensure the greatest possible antitumor activity. Palbociclib inhibits 
DNA synthesis by preventing progression from the G1 to S phase of the cell cycle.  Treatment of tumor 
cells with palbociclib inhibits Rb phosphorylation and induces growth arrest. Accordingly, a reduction in 
Rb phosphorylation serves as a biomarker of CDK4/6 inhibition by palbociclib. 
 
Eligible patients will receive a single cycle of re-induction therapy. Palbociclib will be administered 
once daily for 21 days in combination with an established 4-drug re-induction platform.  After 
completion of the feasibility portion of the study an expanded cohort will be enrolled at the MTD and/or 
recommended phase 2 dose (RP2D) of palbociclib to further assess the safety and feasibility of this 
regimen and to preliminarily explore the biological and clinical activity within the confines of a phase 1 
study.  
 
 
 
 
 
 
 
 
 


 
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EXPERIMENTAL DESIGN SCHEMA 
 
Therapy will be interrupted if there is evidence of progressive disease or drug related dose-
limiting toxicity.  Each patient will receive a single cycle of therapy. 
 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
 
Primary Aims 
 
 
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose (RP2D) of palbociclib administered in combination with re-induction 
chemotherapy in pediatric patients with relapsed B- or T-lineage ALL/LL. 
 
 
To define and describe the toxicities of palbociclib administered on this schedule. 
 
 
To characterize the pharmacokinetics of palbociclib in pediatric patients with 
relapsed B- or T-lineage ALL/LL. 
 
 
Secondary Aims 
 
 
To preliminarily define the antitumor activity of palbociclib in combination with 
chemotherapy for children with relapsed ALL/LL within the confines of a Phase 
1 study. 
 
 
To assess the biologic activity of palbociclib in this patient population. 
 
 
2.0 
BACKGROUND 
 
 
Introduction/Rationale for Development 
Disrupted cell cycle regulation is a hallmark of cancer and targeting the cell cycle 
machinery has been an approach taken to treat a broad spectrum of malignancies.  The 
cell cycle is divided into G1 (pre-DNA synthesis), S (DNA synthesis), G2 (pre-division) 
and M (cell division) phases and the transition through these phases is regulated by 
cyclins and cyclin-dependent kinases (CDKs).  Upon mitogenic stimulation, cyclins 


 
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engage CDKs, leading to their activation. D-type cyclins are input-sensing proteins that 
directly receive mitogenic signals. Cyclin D molecules, like all canonical cyclins, feature 
a cyclin box motif that contains important residues for directly engaging CDKs, and it is 
through this interaction that catalytic activity is conferred to the CDK. 
 
D-type cyclins associate with either CDK4 or CDK6, which share extensive homology.  
CDK4 is the key regulator of the G1-S transition. In complex with Cyclin D, CDK4 
phosphorylates retinoblastoma protein (Rb) and drives cell cycle progression, a process 
inhibited by p16INK4A (CDKN2A).1  With this background and rationale, a number of 
CDK inhibitors have been developed for the treatment of cancers that show activation of 
the cyclin D–CDK4/6–INK4–Rb pathway.  Palbociclib (formerly PD-0332991) is an 
orally active small molecule produced by Pfizer that potently and specifically inhibits 
CDK4 and CDK6 leading to cell cycle arrest and this agent is currently used to treat wide 
range of cancers in adults.  
 
Acute lymphoblastic leukemia (ALL) survival now approaches 90% for children using 
conventional cytotoxic agents, but at a cost of cumulative toxicities and late effects. 
Despite improvements in outcomes for children with B- and T lymphoblastic leukemia 
(B-ALL and T-ALL) in recent years, the outcome of patients with primary resistant or 
relapsed disease remains very poor, particularly for children with second or greater 
relapses, refractory disease or T-cell disease. 2  Remission re-induction rates for this 
population are less than 40% and very few children survive long term. 3,4 Therefore, 
current research efforts are focused on a better understanding of the molecular 
pathogenesis of these diseases in order to identify drug targets that may facilitate the 
development of more effective and less toxic tumor-specific therapies.  
 
 
Preclinical Studies 
 
 
Antitumor Activity 
Preclinical studies in ALL summarized below describe the essential role of cyclin 
D3 in T-ALL initiation and progression. These studies have also demonstrated 
that targeting of the CDK4/6 complex using palbociclib, can suppress ALL 
proliferation and lead to efficient cell death and disease remission in animal 
models of the disease and in human disease transplant settings.   
 
CCND3 is over-expressed in T-ALL and is essential for disease initiation 
and progression. Sicinska et al. have previously shown that Ccnd2 (Cyclin D2) 
and Ccnd3 (Cyclin D3) are expressed during lymphocyte differentiation and 
that they play different roles in this process. 5 To prove the functional 
connection between Ccnd3 overexpression and T-ALL growth, its expression 
has been silenced in a large number of human T-ALL cell lines, the majority of 
which carry NOTCH1 mutations. Ccnd3 silencing impacted tumor cell growth 
due to significant inhibition of cell cycle progression (S phase entry). Further, in 
a transplantation model of NOTCH-driven T ALL deletion of Ccnd3 (Ccnd3-/-) 
failed to induce leukemia whereas Ccnd3 expressing progenitors led to 
induction of disease that rapidly progressed and killed all recipients by week 
10-post transplantation. Normal peripheral T-cells lacking Ccnd3 could be 
detected but these cells showed no signs of transformation. These studies were 
the first to identify an essential role for Ccnd3 function in T-ALL. 5 
 
 


 
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Targeting Ccnd3:CDK4/6 complexes using a small molecule inhibitor. To 
determine whether pharmacological inhibition of cyclin D3:CDK4/6 complexes 
could prove beneficial for the targeting of T-ALL, Aifantis and colleagues 
treated 15 human and mouse T-ALL cell lines (Fig. 1A), as well as primary T-
ALL cells (not shown) with PD-0332991, an orally active small molecule that 
potently and specifically inhibits CDK4 and CDK6. 6 They demonstrated that 
PD-0332991 is active at low concentrations (0.5µM) and has the ability to very 
efficiently suppress S-phase entry, leading to proliferation defects. All lines, 
including those in which T-ALL was driven by both NOTCH1 and TAL1 
oncogenes, were sensitive to PD-0332991 treatment. Further biochemical 
studies were consistent with the cell cycle effects demonstrating specific loss of 
phosphorylated Rb (pRb) and hyper-phosphorylation and accumulation of the 
CDK inhibitor p27 (Fig. 1B). Furthermore, mixing of PD-0332991 treated and 
untreated T-ALL cells in vitro proved the cytostatic effects of the treatment. 
Gene expression analysis of T-ALL lines treated with the inhibitor further 
supported the specific targeting of the S phase entry machinery in these cells 
(Fig. 1C). In addition to these in vitro studies, Aifantis and colleagues also 
treated T-ALL animal models with PD-0332991. There was a dramatic response 
to the drug treatment (Fig. 1D-G) in vivo as demonstrated initially by the 
prolongation of life for the treated animals. Drug treatment led to a significant 
drop in blood counts, splenomegaly, tissue infiltration and overall disease 
regression. Surprisingly, PD-0332991 treatment appeared to induce apoptosis of 
leukemic cells (Figure 1G), explaining the rapid response to the treatment. 
These were exciting and promising findings and suggested strongly that anti-
CDK4/6 treatment could be a very promising way to target T-ALL. 6 
 
CDK4/6 pharmacologic inhibition in B and T-lineage ALL and in 
combination with chemotherapy. To determine the effects of CDK4/6 
pharmacologic inhibition more broadly in ALL, we expanded studies to include 
B-lineage ALL and also investigated CDK4/6 inhibition in combination with 
chemotherapy.  B leukemic cell lines (Reh, RS4, UOCB1, Nalm-6) were each 
treated with 1 µM PD-0332991 for 24 hours.  Cell cycle changes were 
determined by proliferation assays with bromodeoxyuridine (BrdU). Cells were 
labeled with propidium iodide and anti-BrdU antibody, then evaluated by 
fluorescence-activated cell sorting (FACS) using a FACScan flow cytometer 
(BD Scientific).  Treatment with PD-0332991 induced G1 phase cell cycle 
arrest with the percentage of cells in S phase decreased by more than 80% in all 
B-ALL cell lines evaluated (Fig.2). 
 


 
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Cell lines also consistently showed a decrease in pRb and an increase in p27 following 
treatment with PD-0332991 (Fig.3). As an extension of these studies in cell lines, a 
panel of primary T-ALL and B-ALL xenografts have been established. Sources of T-
ALL cells for these xenografts were identified from the Children’s Oncology Group 
(COG) Cell Bank and all human cells have been sequenced.  Disease regression has 
been observed following treatment for 5 days with PD-0332991 in both B- and T-
lineage ALL xenografts (Fig. 4). Combinations of chemotherapy with palbociclib have 
also been delivered in T and B-ALL xenografts.  To determine the impact of drug 
sequence, xenografts were treated on two different schedules:  palbociclib days 1-5 
Figure 1. The PD-0332991 inhibitor suppresses T-ALL growth. PD-
0332991 efficiently suppresses cell cycle entry in human T-ALL cell lines 
(A). B) PD-0332991 blocks S phase entry by affecting Rb 
phosphorylation and p27 (Cdkn1b) degradation. C) Molecular response 
to PD-0332991 in human T-ALL cells, demonstrating effects on cell cycle 
regulators. D) Overall survival of different animal cohorts after 10 
consecutive days of treatment. Significant effects on spleen size (E) and 
tissue infiltration (F) are shown, 2 weeks post treatment. (G) Induction of 
cell death in leukemia cells in response to inhibitor treatment. Annexin 
staining in liver and lung T-ALL cells is shown.  
Figure 2. Cell cycle changes after 24 hours of 
treatment with PD-0332991. 
Figure 3. pRb and p27 expression after 24 hours 
of treatment with PD-0332991. 


 
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followed by chemotherapy with vincristine, Erwinia asparaginase or dexamethasone 
starting on day 8, or concomitant administration of palbociclib and chemotherapy.  No 
antagonism was observed with either dose schedule and a more significant reduction in 
disease burden was observed when palbociclib and chemotherapy were administered 
concomitantly (Fig. 5). 
 
 
 
 
 
Figure 4. Reduction in disease burden following 5 days of treatment with PD-0332991 
 in T-ALL (A) and B-ALL (B) xenografts. 
Figure 5. Significant added reduction in disease burden following concomitant treatment with palbociclib plus 
chemotherapy in T-ALL (A) and B-ALL (B, C and D) xenografts. 


 
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Animal Toxicology 
Palbociclib has been evaluated in toxicology and safety pharmacology studies of 
up to 39 weeks in duration (see Investigator Brochure for detailed information). 
The primary palbociclib toxicities in preclinical studies were to the bone marrow, 
lymphoid tissues, and testes. These toxicities occurred in both rats and dogs and 
are consistent with cell cycle inhibition produced by the drug. Bone marrow 
pancytopenia resulted in decreases in various hematology parameters; however, 
the changes were reversible following cessation of dosing. Reversible 
myelosuppression is anticipated in clinical studies and may be dose-limiting. 
Palbociclib demonstrated a potential for aneugenicity in the in vitro and in vivo 
micronucleus assays. In addition, palbociclib was determined non-phototoxic.   
 
 
Preclinical Pharmacokinetic Studies 
In nonclinical species (rat, dog, and monkey), palbociclib exhibits low to 
moderate plasma clearance, large volume of distribution, and moderate oral 
bioavailability ranging from 23% to 56%. Plasma protein binding of palbociclib 
is moderate in mouse, rat, rabbit, dog, and human plasma. Radioequivalents were 
widely distributed to most rat tissues and fluids following an oral dose of 
[14C]palbociclib, with radioactivity levels consistently greater than those 
observed in blood. In vitro, palbociclib is primarily metabolized by cytochrome 
P450 (CYP)3A and sulfotransferase (SULT) 2A1 enzymes. The major primary 
metabolic pathways for [14C]palbociclib in rats and humans involved sulfonation 
and oxidation. In rats and dogs, [14C]palbociclib was mainly eliminated via the 
feces; the high fecal elimination occurred via biliary excretion in rats. Palbociclib 
and its oxidative metabolite, PF-05089326, demonstrated little or no inhibition of 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 enzyme 
activities and thus, showed low potential for CYP-mediated pharmacokinetic 
drug interactions. However, palbociclib and PF-05089326 caused time dependent 
inhibition of CYP3A midazolam 1-hydroxylase and testosterone 6β-
hydroxylase activities and may have the potential for pharmacokinetic drug 
interactions with compounds for which CYP3A-mediated metabolism constitutes 
the primary mechanism of clearance. Palbociclib did not cause induction of 
CYP1A2, CYP2B6, CYP2C8, or CYP3A4 mRNA expression and/or enzyme 
activity in vitro in human hepatocytes; thus, the potential for palbociclib to 
induce these enzymes is considered to be low at clinically relevant 
concentrations. The potential for palbociclib to inhibit uridine diphosphate 
glucuronosyltransferase (UGT) enzymes (UGT1A1, UGT1A4, UGT1A6, 
UGT1A9, and UGT2B7) was assessed and the likelihood of drug-drug 
interaction (DDI) at clinically relevant concentrations is considered low. Overall, 
based on the in vitro results, palbociclib showed a low potential to inhibit P-
glycoprotein (P-gp) (systemically), breast cancer resistance protein (BCRP) 
(systemically), organic anion transporting polypeptide (OATP)1B1, OATP1B3, 
bile salt export pump (BSEP), organic anion transporter (OAT)1, OAT3, and 
organic cation transporter (OCT)2 at clinically relevant concentrations. However, 
palbociclib has the potential to inhibit OCT1 at clinically relevant concentrations, 
as well as the potential to inhibit P-gp or BCRP in the GI tract at the proposed 
clinical dose. Additional details are included in the Investigator Brochure. 
 
 
 
 


 
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Adult Studies 
Palbociclib has been studied as monotherapy or in combination with other agents in 
several clinical trials for adults with advanced Rb-expressing hematopoietic and solid 
tumors and it has been well tolerated with dose limiting toxicities of neutropenia and 
thrombocytopenia. The recommended dose in adults is 125 mg orally once daily for 21 
consecutive days in 28-day cycles. Palbociclib has been most extensively studied in post-
menopausal women with estrogen-receptor (ER)-positive, human epidermal growth 
factor receptor (HER) 2-negative advanced breast cancer.  Palbociclib received 
accelerated approval in the US in February 2015 for first-line systemic treatment of post-
menopausal women with ER-positive, HER2-negative locally advanced or metastatic 
breast cancer and investigation in other malignancies is presently underway.7  The 
approval of palbociclib was based on the phase 2 PALOMA-1/TRIO-18 study, where 165 
patients were randomized to palbociclib plus letrozole vs. letrozole alone.8 Median 
progression-free survival (PFS) was 10.2 months for the letrozole group and 20.2 months 
for the palbociclib plus letrozole group (p=0.0004). These results were confirmed in a 
double-blind randomized phase 3 trial in 666 post-menopausal women with ER-positive, 
HER2-negative locally advanced or metastatic breast cancer. 9 The median PFS was 24.8 
months in the palbociclib-letrozole group vs. 14.5 months in the placebo-letrozole group 
(p<0.001).  Therapy was well tolerated and the most common treatment-related adverse 
events in the palbociclib arm were neutropenia, leukopenia, anemia and fatigue. In 
February 2016, the FDA granted an expanded indication for palbociclib for women with 
ER-positive, HER2-negative metastatic breast cancer that progressed after prior 
endocrine therapy after the PALOMA-3 randomized phase 3 trial demonstrated that 
palbociclib and fulvestrant were associated with a significant improvement in PFS 
compared with fulvestrant plus placebo (median PFS 9.5 months vs. 4.6 months; 
p<0.0001). 10 While palbociclib has been studied most extensively in combination with 
hormone therapy, it has also been studied in combination with paclitaxel in metastatic 
breast cancer. This regimen was well tolerated and prolonged tumor responses were 
observed. 11 
 
 
Pediatric Studies 
 
 
Prior Experience in Children  
There has been one pediatric study of palbociclib (PBTC 042; NCT02255461) to 
date. The phase 1 single agent trial of palbociclib in children with Rb-positive 
relapsed, progressive or refractory central nervous system (CNS) tumors 
conducted by the Pediatric Brain Tumor Consortium opened in October 2014. 12 
Patients aged 4-21 years are eligible and the starting dose level for this trial was 
50 mg/m2/day of palbociclib for 21 days consecutively in 28 day cycles for up to 
2 years.  Among 14 evaluable patients, grade 4 neutropenia in 2 of 4 patients 
treated at 95 mg/m2/day (dose level 3) was the only observed dose limiting 
toxicity (DLT).  The maximum tolerated dose (MTD) was defined as 75 
mg/m2/day and the trial is currently enrolling an expansion cohort at this dose.  
Enrollment will also be expanded to include a cohort of more heavily pre-treated 
patients, who have received more than 4 prior regimens at a starting dose of 50 
mg/m2/day.   
 
 
 
Overview of Proposed Pediatric Study 
AINV18P1 is a pilot study where palbociclib will be administrated in combination with a 
standard re-induction platform in pediatric relapsed ALL and lymphoblastic lymphoma 


 
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(LL). LL patients are included because the patient population is rare and these patients 
are most commonly treated with ALL regimens.  Based on the current pediatric phase 1 
trial investigating palbociclib in children with CNS tumors (NCT02255461), the 
proposed starting dose for this study will be 50 mg/m2/day for 21 days. Although the 
MTD was defined as 75 mg/m2/day, this was in non-heavily pretreated patients and a 
cohort of more heavily pre-treated patients is currently enrolling at a dose of 50 
mg/m2/day, which is approximately 70% of the recommended dose in adults.  Since the 
most common DLT for palbociclib to date has been myelosuppression and palbociclib 
will be given in combination with cytotoxic chemotherapy, this trial will start at the lower 
50 mg/m2/day dose level.  A pediatric formulation is available. 
 
Block 1 therapy from COG AALL01P2 13 was selected as the re-induction platform for 
this study because this regimen has a well-established response, safety and feasibility 
track record in studies we have conducted previously, both alone and in combination with 
novel agents.14,15 The only modification that has been made to this regimen is reducing 
the number of doses of pegaspargase from 4 to 2 in an effort to minimize the risk for 
toxicity, particularly among the adolescent and young adult patients.  Prior preclinical 
studies have shown that pretreatment with palbociclib led to synchronous S phase entry 
and a potentiation of the response to the administration of subsequent cytarabine. 16 
However, our preclinical studies in B- and T-ALL xenografts have shown more 
significant reduction in leukemic burden when palbociclib was given with chemotherapy 
concomitantly vs. sequentially (Fig. 5) and this is in agreement with preclinical studies in 
solid tumors in adults (personal communication, Pfizer).  
 
The rolling six trial design will be used for dose determination in this study.17 Per this 
design, if 2 or more of a cohort of up to 6 patients experience dose-limiting toxicity 
(DLT) at the initial dose level, then the MTD has been exceeded and a single dose de-
escalation will be conducted. The DLT observation period for the purposes of dose 
confirmation will be the first cycle of therapy. We plan to study no more than 2 dose 
levels. After completion of the feasibility portion of the study an expanded cohort will be 
enrolled at the MTD and/or recommended phase 2 dose (RP2D) of palbociclib to further 
assess the safety and feasibility of this regimen and to preliminarily explore the biological 
and clinical activity within the confines of a pilot study.  Patients with relapsed B and T-
ALL/LL will be eligible and study treatment will consist of a single cycle of palbociclib 
in combination with chemotherapy. 
 
 
 


 
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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
 
Current Study Status  
Investigators should refer to the COG website to determine if the study is currently open 
for accrual. If the study is listed as active, investigators should then access the Studies 
Requiring Reservations page to ensure that a reservation for the study is available. To 
access the Studies Requiring Reservations page:  
1. Log in to https://www.cogmembers.org. 
2. From the menu bar, click eRDES. The eRDES sub-menu appears. 
3. Click Reservation. The Studies requiring Reservations page appears. 
 
 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling 
patients. Sites must submit IRB/REB approvals to the COG Operations Regulatory email 
and allow 3 business days for processing. The submission must include a fax coversheet 
and the IRB approval document(s) emailed (COG email address TBD). When a site has a 
pending patient enrollment within the next 24 hours, this is considered a “Time of Need” 
registration. For Time of Need registrations, in addition to marking your submissions as 
‘URGENT’. 
 
 
Patient Registration 
Prior to enrollment on study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry in the OPEN system (https://open.ctsu.org/open
/logonForm.open) once authorization for the release of protected health information 
(PHI) has been obtained. To register a patient or update an existing registry record in the 
COG Patient Registry, please go to the OPEN Portal at https://open.ctsu.org and click the 
COG Patient Registry link on OPEN’s Welcome screen. 
 
 
Reservation and Contact Requirements 
Prior to enrolling a patient on study, a reservation must be made through the OPEN 
website and the Study Chair or Vice Chair should be notified. (The patient will need a 
COG patient ID number in order to obtain a reservation). Patients must be enrolled within 
7 calendar days of making a reservation.  
 
Reservations may be obtained 24-hours a day through the COG website. Please refer to 
the Reservation System eRDES User Guide that can be downloaded at: 
https://cogmembers.org/site/help/defaultUserguides.aspx   
 
 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to 
institutional guidelines. 
 
 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this 
trial must only be done after obtaining written informed consent.  This can be 
accomplished through the study-specific protocol.  Documentation of the informed 
consent for screening will be maintained in the patient’s research chart. Studies or 
procedures that were performed for clinical indications (not exclusively to determine 


 
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eligibility) may be used for baseline values even if the studies were done before informed 
consent was obtained. 
 
 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 
into RAVE immediately following enrollment. 
 
 
Institutional Pathology Report 
Immediately following enrollment, the institutional pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into RAVE. The report must 
include the associated study number and COG patient registration and accession 
numbers. Personal identifiers, including the patient’s name and initials must be removed 
from the institutional pathology report prior to submission. 
 
 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Patients who give informed consent for the protocol in order to undergo 
screening for eligibility are not considered enrolled and should not be enrolled until the 
screening is completed and they are determined to meet all eligibility criteria. Study 
enrollment is accomplished by going to the Enrollment application in the eRDES system. 
(https://cogmembers.org/apps/erdes) If you have problems with enrollment, refer to 
online help in the Applications area of the COG website. Patients must be enrolled before 
treatment begins with the exception of Day 1 intrathecal chemotherapy, which can be 
administered at the time of the diagnostic LP. The date protocol therapy is projected to 
start must be no later than five (5) calendar days after the date of study enrollment. 
Patients must not receive any protocol therapy prior to enrollment. 
 
 
Dose Assignment 
The dose level will be assigned via eRDES at the time of study enrollment. 
 
 
4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior 
to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no 
older than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy 
starts within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value 
is outside the limits of eligibility, or laboratory values are older than 7 days, then the following 
laboratory evaluations must be re-checked within 48 hours prior to initiating therapy: bilirubin, 
ALT (SGPT) and serum creatinine.  If the recheck is outside the limits of eligibility, the patient 
may not receive protocol therapy and will be considered off protocol therapy. Imaging studies, 
bone marrow biopsy and/or aspirate must be obtained within 14 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last 
day of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that 
type of prior therapy, then that patient cannot be enrolled until September 8th.   
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived.  All clinical and laboratory data required for determining eligibility of a patient 


 
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enrolled on this trial must be available in the patient’s medical or research record which 
will serve as the source document for verification at the time of audit. 
 
 
Inclusion Criteria 
 
 
Age: Patients must be ≥ 12 months and < 31 years of age at the time of study 
enrollment. 
 
 
Diagnosis: Patients with recurrent or refractory B- or T-lineage lymphoblastic 
leukemia and lymphoma. Patients with leukemia must have > 5% (M2 or M3) 
bone marrow blasts with or without an extramedullary site of relapse. 
Morphologic relapse for M2 should be confirmed using flow cytometry, FISH 
and/or cytogenetics or molecular techniques. Patients with LL must have either 
measurable or evaluable disease. 
 
 
Disease Status: Patients with first or greater relapsed T-lineage ALL or LL and 
second or greater relapsed B-lineage ALL or LL are eligible.  Patients with 
primary refractory disease with at least 2 prior induction attempts or first relapse 
refractory to at least one prior re-induction attempt are eligible. Patients with 
refractory disease, however, must not have received a standard 4-drug re-
induction inclusive of a steroid, anthracycline, asparaginase and vincristine in 
combination (e.g., UKALLR3 or AALL01P2) as their most recent prior therapy 
but they may have received a re-induction regimen that contain some of these 
agents. 
 
 
Performance Level:  Karnofsky ≥ 50% for patients > 16 years of age and Lansky 
≥ 50 for patients ≤ 16 years of age (See Appendix I).  Patients who are unable to 
walk because of paralysis, but who are up in a wheelchair, will be considered 
ambulatory for the purpose of assessing the performance score. 
 
 
Prior Therapy: 
 
 Patients must have fully recovered from the acute toxic effects of 
all prior anti-cancer therapy and must meet the following 
minimum duration from prior anti-cancer directed therapy prior to 
enrollment. If after the required timeframe, the numerical 
eligibility criteria are met, e.g., blood count criteria, the patient is 
considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known 
to be myelosuppressive. See DVL homepage for commercial 
and Phase 1 investigational agent classifications. For agents 
not listed, the duration of this interval must be discussed 
with the study chair and the study-assigned Research 
Coordinator prior to enrollment. 
• 
A waiting period prior to enrollment is not required 
for patients receiving standard cytotoxic 
maintenance chemotherapy (i.e., corticosteroid, 
vincristine, 6MP, and/or methotrexate). 
 


 
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• 
Intrathecal cytotoxic therapy: No waiting period is 
required for patients having received intrathecal 
cytarabine, methotrexate, and/or hydrocortisone. 
Intrathecal chemotherapy given at the time of 
diagnostic LP to evaluate for relapse prior to study 
enrollment is allowed.  
• 
≥ 14 days must have elapsed after the completion of 
other cytotoxic therapy, with the exception of 
hydroxyurea, for patients not receiving standard 
maintenance therapy. Additionally, patients must 
have fully recovered from all acute toxic effects of 
prior therapy. 
 
NOTE: Cytoreduction with hydroxyurea in patients can be 
initiated and continued for up to 24 hours prior to 
the start of protocol therapy.  
 
Note: Intrathecal chemotherapy that is given up to 72 
hours prior to initiation of systemic chemotherapy per 
AINV18P1 counts as protocol therapy and not prior anti-
cancer therapy. Intrathecal chemotherapy given > 72 
hours prior does not count as protocol therapy. 
  
 
b. Anti-cancer agents not known to be myelosuppressive (e.g. 
not associated with reduced platelet or ANC counts): ≥ 7 
days after the last dose of agent. See DVL homepage for 
commercial and Phase 1 investigational agent classifications. 
For agents not listed, the duration of this interval must be 
discussed with the study chair and the study-assigned 
Research Coordinator prior to enrollment.  
 
NOTE: Cytoreduction with prednisone or 
methylprednisolone for ≤ 120 hours (5 days) in 
patients can be initiated and continued for up to 24 
hours prior to the start of protocol therapy.  
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of 
last dose of antibody with the exception of blinatumomab, 
and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. Patients must have been off 
blinatumomab infusion for at least 14 days and all drug 
related toxicity must have resolved to Grade ≤ 1. 
 
d. Corticosteroids: See Section 4.2.2.1. If used to modify 
immune adverse events related to prior therapy, ≥ 14 days 
must have elapsed since last dose of corticosteroid and 
toxicity related to prior immune therapy must be recovered 
to Grade ≤ 1 off corticosteroids. 
 
e. Hematopoietic growth factors: ≥ 14 days after the last dose 
of a long-acting growth factor (e.g. pegfilgrastim) or 7 days 


 
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for short-acting growth factor. For agents that have known 
adverse events occurring beyond 7 days after administration, 
this period must be extended beyond the time during which 
adverse events are known to occur.  The duration of this 
interval must be discussed with the study chair and the 
study-assigned Research Coordinator. 
 
f. Interleukins, Interferons and Cytokines (other than 
Hematopoetic Growth Factors): ≥ 21 days after the 
completion of interleukins, interferon or cytokines (other 
than Hematopoietic Growth Factors) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell 
transplant, or any stem cell infusion including DLI or 
boost infusion: ≥ 84 days after infusion and no evidence 
of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  
≥ 42 days. 
 
h. Cellular Therapy: ≥ 30 days after the completion of any type 
of cellular therapy (e.g. modified T cells, NK cells, dendritic 
cells, etc.) 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days 
after local XRT; ≥ 150 days after TBI, craniospinal XRT or 
if radiation to ≥ 50% of the pelvis; ≥ 42 days if other 
substantial BM radiation. 
 
j. 
Patients must not have received prior exposure to palbociclib 
or another CDK4/6 inhibitor. 
 
 
Organ Function Requirements 
 
 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 


 
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 Adequate Liver Function Defined as: 
- 
bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper 
limit of normal (ULN) for age  
- 
SGPT (ALT) ≤ 225 U/L unless disease-related.  For the 
purpose of this study, the ULN for SGPT is 45 U/L.  
- 
Serum albumin ≥ 2 g/dL. 
 
 Adequate Cardiac Function Defined As: 
- 
Shortening fraction of  ≥ 27% by echocardiogram, or 
- 
Ejection fraction of ≥ 50% by gated radionuclide study. 
 
 
 
Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines.  
 
 
Exclusion Criteria 
 
 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks 
of fetal and teratogenic adverse events as seen in animal/human studies. Based on 
the mechanism of action, palbociclib may be expected to cause fetal harm if used 
during pregnancy. Pregnancy tests must be obtained in girls who are post-
menarche. Males or females of reproductive potential may not participate unless 
they have agreed to use an effective contraceptive method for the duration of 
study therapy. Women of reproductive potential should use effective 
contraception during treatment and for at least 3 weeks after the last dose of 
palbociclib. Males with female partners of reproductive potential should use 
effective contraception during treatment and for 3 months after the last dose of 
palbociclib. Animal data suggests that palbociclib may affect male fertility. 
 
 
Concomitant Medications 
 
 Corticosteroids: Prednisone or methylprednisolone for ≤ 120 hours (5 
days) may be administered for cytoreduction up to 24 hours prior to the 
start of protocol therapy and as treatment for allergic reactions or for 
physiologic replacement/stress dosing of hydrocortisone for documented 
adrenal insufficiency. Corticosteroids are not allowed for other 
indications. If used to modify immune adverse events related to prior 
therapy, ≥ 14 days must have elapsed since last dose of corticosteroid 
(See Section 4.1.6.1.d). 
 
 Investigational Drugs:  Patients who are currently receiving another 
investigational drug. 
 
 Anti-cancer Agents: Patients who are currently receiving other anti-
cancer agents are not eligible [except patients receiving hydroxyurea, 
which may be continued until 24 hours prior to start of protocol therapy]. 
 


 
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 CYP3A4 Agents: Patients who are currently receiving drugs that are 
strong inhibitors and/or inducers of CYP3A4 or sensitive CYP3A4 
substrates and CYP3A4 substrates with a narrow therapeutic range are 
not eligible. Strong inducers or inhibitors of CYP3A4 are prohibited 
from 14 days prior to enrollment to the end of the study. See Appendix 
III for a list of agents. 
 
 Anti-GVHD agents post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant. 
 
 
Patients must be able to swallow intact capsules or liquid.  Patients that are 
unable to swallow oral medications may receive palbociclib oral solution through 
an NG tube. G tube administration is not allowed. 
 
 
Infection: Patients who have an uncontrolled infection defined as below: 
• 
Positive bacterial blood culture within 48 hours of study enrollment; 
• 
Fever above 38.2°C within 48 hours of study enrollment with clinical signs 
of infection. Fever that is determined to be due to tumor burden is allowed if 
patients have documented negative blood cultures for at least 48 hours prior 
to enrollment and no concurrent signs or symptoms of active infection or 
hemodynamic instability. 
• 
A positive fungal culture within 30 days of study enrollment or active 
therapy for presumed invasive fungal infection.  
• 
Patients may be receiving IV or oral antibiotics to complete a course of 
therapy for a prior documented infection as long as cultures have been 
negative for at least 48 hours and signs or symptoms of active infection have 
resolved. For patients with c. difficile diarrhea, at least 72 hours of 
antibacterial therapy must have elapsed and stools must have normalized to 
baseline.  
• 
Active viral or protozoal infection requiring IV treatment.  
 
 
Patients known to have one of the following concomitant genetic syndromes: 
Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, 
Kostmann syndrome, Shwachmann syndrome or any other known bone marrow 
failure syndrome. 
 
 
Patients who in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study. 
 
 
Cumulative prior anthracycline exposure must not exceed 400 mg/m2 of 
DOXOrubicin equivalents. 
 
For the purposes of determining eligibility for this protocol, the following 
cardiotoxicity multipliers will be used to determine DOXOrubicin equivalents:  
 
DOXOrubicin: Multiply total dose x 1  
DAUNOrubicin: Multiply total dose x 0.5  
EpiRUBicin: Multiply total dose x 0.67  
IDArubicin: Multiply total dose x 5  


 
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MitoXANTRONE: Multiply total dose x 4  
 
 
5.0 
TREATMENT PROGRAM 
 
 
Overview of Treatment Plan 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
Palbociclib  
IND# 141416 
PO (or via 
NG- tube) 
DL1: 50 mg/m2 (max 100 mg/day) 
DL-1: 35 mg/m2 (max 75 mg/day) 
 
Once daily on Days 1-21  
 
Intrathecal Cytarabine (IT 
ARAC):  All patients on 
Day 1 (before CNS status 
is known)@ 
IT 
Age (yrs) 
Dose 
1-1.99 
30 mg 
2-2.99 
50 mg 
   ≥3 
70 mg 
 
1@ 
Intrathecal Methotrexate 
(IT MTX):  CNS1 and 2 
 
 
IT 
Age (yrs) 
Dose 
1-1.99 
8 mg 
 2-2.99 
10 mg 
 3-8.99 
12 mg 
    ≥9 
15 mg 
18,32 
Intrathecal Triple Therapy 
(ITT)@: 
Methotrexate (MTX)/ 
Hydrocortisone 
(HC)/Cytarabine (ARAC) if 
CNS3 
 
 
IT 
Age (yrs) 
Dose 
   1-1.99 
MTX:8mg, 
                   HC: 8mg, 
                         ARAC: 16mg 
    2-2.99 
MTX: 10mg 
                   HC: 10 mg 
                       ARAC: 20 mg 
    3-8.99 
MTX: 12 mg 
                  HC: 12 mg 
                       ARAC: 24 mg 
        ≥9 
MTX: 15 mg 
                  HC: 15 mg 
                       ARAC: 30 mg 
1@, 4, 11, 18, 25 
Doxorubicin (DOXO) 
slow IV push 
or infusion 
over 1-15 min 
60 mg/m²/dose 
4 
 
PredniSO(LO)NE (PRED)* 
 
PO  
40 mg/m²/day divided BID or TID 
4-31 
VinCRIStine (VCR) 
IV push or 
mini-bag per 
institutional 
policy 
1.5 mg/m²/dose (MAX dose 2 mg) 
4, 11, 18, 25 
Pegaspargase (PEG-ASP)# 
IV  
over 1-2 
hours 
2500 International units/m²/dose 
5, 18 
* IV methylprednisolone may be given at 80 % of the oral predniSONE or predniSOLONE dose 
# If allergic to PEGaspargase then see Section 6.2.1 for Asparaginase Erwinia Chrysanthemi 
dosing. 
@ Patients with known CNS3 disease at the time of study enrollment may receive triple 
intrathecal chemotherapy on Day 1 as a substitute for intrathecal cytarabine, at the discretion of 
the treating investigator. Patients are NOT to receive both intrathecal triples and intrathecal 
cytarabine on Day 1, regardless of CNS status.    
 
A cycle of therapy is considered to be 32 days.  Please see Therapy Delivery Maps (TDMs) in 
Appendix VI (patients with ALL) and Appendix VII (Patients with LL). 
 
It is recommended that drugs be administered in the order listed below.   


 
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Drug doses should be adjusted based on the BSA calculated from height and weight obtained 
within one week prior to the beginning of protocol therapy. For patients able to swallow capsule, 
please refer to the dosing nomogram in Appendix V-A. Patients unable to swallow capsules 
should use the oral solution, please refer to Appendix V-B. 
 
 
Palbociclib: PO (or via NG- tube) 
 
Days: Once daily on Days 1-21 
Administer with food. Take at approximately the same time each day. Swallow capsules whole, 
do not crush, chew, or open capsules prior to swallowing (do not ingest if capsules are broken, 
cracked, or not fully intact).  The oral solution can be administered without regard to food intake.  
If a patient vomits, an additional dose should not be taken. The next prescribed dose should be 
taken at the usual time. Avoid grapefruit or grapefruit juice for the duration of the protocol 
therapy. It a dose is inadvertently missed, do not make it up. If a dose is missed and the next dose 
is more than 12 hours away, the missed dose should be administered.  If the next dose is less than 
12 hours away, the missed dose should not be administered. Missed doses should not be made up.  
See Appendices V-A and V-B for palbociclib capsule and liquid formulation dosing.  
 
Only use palbociclib provided for investigational use specifically for AINV18P1.  
 
Cytarabine: IT- All patients (before CNS status is known) 
Day 1 
 
Age (yrs) 
Dose 
1-1.99  
30 mg 
2-2.99  
50 mg 
   ≥3 
 
70 mg 
 
Methotrexate: IT - for CNS-negative (CNS1/CNS2) patients only. 
Day 18 and 32. 
 
Aged – based dosing: 
Age (yrs): 
Dose: 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
 
15 mg 
 
Intrathecal Triple Therapy (ITT): Methotrexate (MTX)/Hydrocortisone (HC)/Cytarabine 
(ARAC)-  for CNS3 patients only 
 
Days 1*, 4, 11, 18, 25 
 
 
Age (yrs) 
Dose 
   1-1.99 
MTX:8mg 
                 
 
 
HC: 8mg 
                           
 
ARAC: 16mg 
    
 
   2-2.99 
MTX: 10mg 
                    
 
 
HC: 10 mg 
                         
 
ARAC: 20 mg 
     
 
   3-8.99 
MTX: 12 mg 
                   
 
 
HC: 12 mg 


 
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ARAC: 24 mg 
         
 
     ≥ 9  
MTX: 15 mg 
                   
 
 
HC: 15 mg 
                         
 
ARAC: 30 mg 
 
*Intrathecal triple therapy can be administered on Day 1 instead of intrathecal cytarabine for 
patients already known to be CNS3 at study entry.  
 
 
Doxorubicin: slow IV push or IV infusion over 1-15 minutes 
Day: 4 
Dose: 60 mg/m2/dose   
 
Administer at a concentration not to exceed 2 mg/mL by slow IV push or infusion over 1-15 
minutes. Short infusion times may be lengthened slightly (and 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.  
 
 
PredniSO(LO)NE: PO 
 
Days: 4-31 
 
Dose 40 mg/m2/day divided BID or TID 
Note: If a patient in unable to take predniSONE or predniSOLONE by mouth, IV 
methylprednisolone may be given at 80 % of the oral dose 
 
VinCRIStine: IV push over 1-5 minutes or infusion via minibag as per institutional policy 
Days 4, 11, 18, and 25 
Dose: 1.5 mg/m2/dose (maximum dose 2 mg). 
 
Special precautions: vinCRIStine: FOR INTRAVENOUS USE ONLY. 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing the 
statement “Do not remove covering until moment of injection. For intravenous use only - Fatal if 
given by other routes.”  
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate liposomal injection, 
VSLI, Marqibo®). Use conventional vincristine only; the conventional and liposomal 
formulations are NOT interchangeable. 
 
PEGaspargase: IV over 1-2 hours 
Days 5 and 18.  
Dose: 2,500 International units/m2/dose. 
Administer IV infusion through the tubing of a rapidly infusing solution of D5W or 0.9% NaCl. 
Use anaphylaxis precautions per institutional policy.  Observe patient for at least ONE hour after 
administration for signs of hypersensitivity reactions. 
 
#If allergic to PEGaspargase then see Section 6.2.1 for Asparaginase Erwinia 
Chrysanthemi dosing. 
 


 
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Special precautions: 
1. Pegaspargase is contraindicated with a history of severe pancreatitis with any prior 
asparaginase therapy. Caution should be used if serious thrombosis or hemorrhagic events 
have occurred with any prior asparaginase therapy. 
2. Pegaspargase may affect coagulation factors and predispose to bleeding and/or thrombosis. 
Caution should be used when administering any concurrent anticoagulant therapy. 
3. Suggested monitoring during and after administration: Because pegaspargase is long acting, 
hypersensitivity reactions may not appear for hours after drug administration. Monitor vital 
signs, for signs of fever, chills, or acute allergic reactions including anaphylaxis. Have 
medications to treat hypersensitivity reactions readily available at each administration (e.g., 
epinephrine, IV corticosteroids, antihistamines). Consider prescribing an EpiPen® for home 
use. 
 
DUE TO A SIGNIFICANTLY INCREASED RISK OF MORBIDITY AND MORTALITY IN 
CHILDREN WITH MULTIPLY RELAPSED ALL UNDERGOING INTENSIVE THERAPY, 
HOSPITALIZATION FROM INITIATION OF THERAPY IS STRONGLY RECOMMENDED. 
 
 
Dosing Schema 
 
 
Inter-Patient Dosing Schema 
 
Dose Level 
Palbociclib (mg/m2) 
Palbociclib max 
dose (mg/day) 
-1 
35 
75 
   1*  
50 
100 
 
If the MTD has been exceeded at the first dose level, then the subsequent cohort 
of patients will be treated at a dose of 35 mg/m2 (Dose Level -1). If Dose Level -
1 is not well tolerated, further de-escalation will not occur. The study will be 
closed to accrual. 
 
See Appendix V-A and Appendix V-B for palbociclib capsule and liquid 
formulation dosing.  
 
 
Intra-Patient Escalation 
Intra-patient dose escalation is not allowed.  
 
 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP website (http://ctep.cancer.gov). Any suspected or 
confirmed dose-limiting toxicity should be reported immediately (within 24 hours) to the 
Study Chair. 
 
 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or 
definitely attributable to palbociclib.  The DLT observation period for the purposes of 
dose-confirmation will be the first cycle of therapy. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.   


 
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Non-hematological dose-limiting toxicity attributable to palbociclib 
 Any Grade 3 or greater non-hematological toxicity possibly, 
probably  or definitely  attributable to palbociclib  with the specific 
exclusion of: 
• 
Grade 3 nausea, anorexia, fatigue, malaise, weight loss, 
vomiting or diarrhea that returns to ≤ Grade 2 or baseline 
within 3 days with supportive care  
• 
Grade 3 or 4 liver enzyme elevation, including 
ALT/AST/GGT, that returns to Grade ≤ 2 within 42 days of 
the start of therapy. Note:  For the purposes of this study the 
ULN for ALT is defined as 45 U/L. Adverse event grades 
will be based on increases above the upper limit of normal, 
regardless of the subject’s baseline. See Appendix XI for 
toxicity grading table 
• 
Grade 3 direct bilirubin elevation that is asymptomatic and 
returns to ≤ Grade 1 within 42 days of the start of therapy 
• 
Grade 3 total bilirubin elevation that resolves to ≤ Grade 1 
within 42 days of the start of therapy 
• 
Grade 3 or 4 fever, febrile neutropenia or infections with or 
without hospitalization  
• 
Grade 3 or 4 hypotension explained by sepsis 
• 
Grade 3 or 4 isolated electrolyte abnormalities that resolve, 
with or without intervention, to ≤ Grade 2 within 3 days. 
Electrolyte supplementation is encouraged.  
• 
Grade 3 tumor lysis syndrome that resolves to ≤ Grade 2 
within 3 days 
• 
Grade 3 mucositis that resolves to ≤ Grade 2 within 3 days 
• 
Grade 3 epistaxis  
• 
Grade 3 bone and/or pain in extremity 
• 
If a patient requires more than 4 doses of palbociclib to be 
held due to toxicity this is a DLT. 
  
 Any Grade 2 non-hematological toxicity that persists for ≥ 7 days 
and is considered sufficiently medically significant or sufficiently 
intolerable by patients that it requires treatment interruption. 
 
 Note: Allergic reactions that necessitate discontinuation of study 
drug will not be considered a dose-limiting toxicity. 
 
 
Hematological dose limiting toxicity 
DLT will be defined as failure to recover a peripheral ANC > 500/mm3 and 
platelets > 20,000/mm3 by 42 days after the first treatment day, not due to 
malignant infiltration. 
 
 Note:  Grade 3 or 4 febrile neutropenia will not be considered a dose-
limiting toxicity. 
 
 


 
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6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
 
 
 
Dose Modifications for Non-Hematological Toxicity Attributable to Palbociclib 
 
 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.4.1, palbociclib will be held until the toxicity is ≤ Grade 1 or as 
otherwise indicated below (see Section 6.2 for dose modifications for other 
backbone chemotherapy agents). When the toxicity resolves to meet eligibility 
parameters or baseline within 14 days of drug discontinuation, the patient may 
resume treatment at the next lower dose level. For patients enrolled at Dose Level 
-1, palbociclib should be discontinued but the backbone chemotherapy can be 
continued if this is not contributing to the toxicity.  Doses reduced for toxicity 
will not be re-escalated, even if there is minimal or no toxicity with the reduced 
dose.  Missed doses will not be made up. 
 
 
If toxicity does not resolve to meet eligibility or baseline parameters within 14 
days of drug discontinuation, the patient must be removed from protocol therapy. 
 
 
If a dose-limiting toxicity recurs in a patient who has resumed treatment at the 
reduced dose level, the patient must be removed from protocol therapy. 
 
 
Dose Modifications for Specific Toxicities Defined Per Drug 
 
Notify the Study Chair at the time of removing a patient from protocol therapy for 
toxicity. The drugs are listed in alphabetical order. 
  
 
Asparaginase [Pegaspargase (PEG-Asparaginase) or Erwinia] 
 
  Allergy 
Systemic Allergic Reactions/Anaphylaxis:  
For severe allergic reaction, discontinue pegaspargase and 
substitute Asparaginase Erwinia (Erwinia). Erwinia therapy 
should begin within 72 hours of the pegaspargase reaction or as 
soon as possible. Erwinia dosing: 25,000 international units 
(IU)/m2 IM/IV M-W-F for six doses substituted for each dose of 
pegaspargase.  If Erwinia is given IV it should be given as a 1-2 
hour infusion.  
 
For mild-moderate reversible reaction: 
1. If the infusion was completed, consider sending an 
asparaginase activity level.  Note that an asparaginase level of at 
least 0.1 IU/ml 14 days after administration is considered 
therapeutic.  There are several reports that suggest different 
thresholds for switching to Asparaginase Erwinia; after 
evaluating these, the following guidelines are recommended for 


 
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consideration to switch to Asparaginase Erwinia, but decisions 
are ultimately up to the treating clinician. 
2. If the infusion was discontinued early, consider re-challenging 
with pegaspargase after premedication and send asparaginase 
levels as above.   
Premedication with antihistamines in the absence of prior 
hypersensitivity has been discouraged in the past since 
antihistamine use may mask the appearance of systemic allergy 
and fail to alert the provider of the presence of asparaginase 
neutralizing antibodies. The use of asparaginase activity assays, 
as described above, are now commercially available and may 
help determine if neutralizing antibodies are present, thus the use 
of premedications is left to the discretion of the provider.   
If there is a question of silent inactivation, check levels as 
described above between 1 hour and 7 days after the dose. 
Subsequent doses of asparaginase should be changed to 
asparaginase Erwinia based on the activity levels described 
above. Whether the dose after which levels were checked should 
be substituted with asparaginase Erwinia will depend on when 
the results are received, the patient’s clinical status, and what 
other therapy is being administered, and is ultimately left to the 
discretion of the treating physician. Of note, asparaginase 
Erwinia is recommended only for pegaspargase hypersensitivity 
reactions and/or in the presence of silent antibody. It is not 
recommended as a substitute for pancreatitis, transaminitis, 
hyperbilirubinemia, coagulation abnormalities, or other 
non-hypersensitivity toxicities associated with pegaspargase.  
 
 Coagulopathy/bleeding: 
If symptomatic, hold asparaginase until symptoms resolve, then 
resume with the next scheduled dose. Consider factor 
replacement (FFP, cryoprecipitate, factor VIIa). Do not withhold 
dose for abnormal laboratory findings without clinical 
symptoms.  
 
  Hyperbilirubinemia:  
Asparaginase may need to be withheld in patients with an 
elevated direct bilirubin, since asparaginase has been associated 
with hepatic toxicity. No specific dose adjustment guidelines are 
provided in the manufacturer’s labeling. Below are proposed 
dose adjustment guidelines from published literature18: 
 
Time point after completion of 
pegaspargase infusion 
Asparaginase activity level 
Action 
1 hour – 1 day 
< 0.5 IU/mL 
Substitute asparaginase Erwinia 
7 days 
< 0.3 IU/mL 
Substitute asparaginase Erwinia 
14 days 
< 0.1 IU/mL 
Substitute asparaginase Erwinia 


 
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Direct 
Bilirubin* 
Dose Modification for Asparaginase [Pegaspargase (PEG-Asparaginase) or 
Erwinia 
< 3.0 
mg/dl 
Full dose 
3.1 – 5.0 
mg/dl 
Hold pegaspargase and resume when direct bilirubin is < 2 mg/dl 
> 5.1 
mg/dl 
Hold the dose of pegasparagase; do not substitute other asparaginase 
products; do not make up the missed dose 
 
 
 
*Refer to Appendix XI for guidelines 
 
  Hyperglycemia: 
Do not modify dose. Treat hyperglycemia as medically 
indicated. 
 
  Hyperlipidemia:  
Do not modify dose. Treat hyperlipidemia as medically 
indicated.  
 
 Ketoacidosis:  
Hold asparaginase until blood glucose can be regulated with 
insulin. 
 
  Pancreatitis: 
Discontinue asparaginase in the presence of Grade 3 or 4 
pancreatitis. In the case of asymptomatic Grade 2 pancreatitis 
(enzyme elevation or radiologic findings only), asparaginase 
should be held until amylase/lipase levels return to normal, 
and/or other signs subside, and then resumed.  
 
 Thrombosis (including CNS and non-CNS events): Withhold 
asparaginase until acute symptoms resolve and treat with 
appropriate antithrombotic therapy and consider repletion of AT-
III, as indicated. Upon resolution of symptoms, consider resuming 
asparaginase while continuing low molecular weight heparin 
(LMWH) or antithrombotic therapy. Consider measurement and 
repletion of AT-III during subsequent courses of asparaginase if 
unable to achieve therapeutic Anti-Xa levels. For significant 
thrombosis (not catheter-related) consider evaluation for inherited 
predisposition to thrombosis. 
 
 
Doxorubicin (Anthracyclines) 
Consider Dexrazoxane prior to each dose for patients with: 
• Anticipated cumulative anthracycline dose > 250 mg/m2 of 
DOXOrubicin equivalent.  
 
Anthracycline Dose Conversion: 
DOXOrubicin: Multiply total dose x 1  
DAUNOrubicin: Multiply total dose x 0.5  


 
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EpiRUBicin: Multiply total dose x 0.67  
IDArubicin: Multiply total dose x 5  
MitoXANTRONE: Multiply total dose x 4  
 
• Past or anticipated radiation with potential impact to the heart (radiation 
to chest, abdomen, spine, or TBI).  
• Recommended dose of dexrazoxane is 10 x the DOXOrubicin dose 
given over 5-15 minutes immediately before the chemotherapeutic agent.  
 
 Monitoring Cardiac Echocardiogram: 
At baseline and then recommended after cumulative dose of 175, 
300, 375, and 450 mg/m2. Please see COG Long Term Follow 
Up Guidelines for additional monitoring recommendations at  
http://www.survivorshipguidelines.org/pdf/2018/COG_LTFU_G
uidelines_v5.pdf  
 
  Dose modification for cardiac toxicity: 
If left ventricular ejection fraction (EF) < 50% (as determined by 
the Biplane Simpson method), or if EF inevaluable shortening 
fraction (SF) < 24%, hold the anthracycline or anthracenedione 
and repeat the echocardiogram in one week.  If EF remains < 
50% (or if EF inevaluable, SF < 24%), discontinue the 
anthracycline or anthracenedione and deliver alternate therapy as 
per the protocol or provider decision.  Resuming cardiotoxic 
therapy depends on the cause of the cardiac dysfunction and the 
results of further cardiac evaluation.   
 
 Myelosuppression:  
If patient has severe infection or severe mucositis, consider 
modifying or omitting anthracycline.  
 
 Hyperbilirubinemia:  
 
Direct Bilirubin 
Dose Adjustment  
< 3.0 mg/dl 
Full dose 
3.1 – 5.0 mg/dl 
Administer 50% of calculated dose 
5.1 – 6.0 mg/dl 
Administer 25% of calculated dose 
> 6.0 mg/dl 
Withhold dose and administer next scheduled dose if toxicity has resolved. 
Do not make up missed doses. 
                         *Refer to Appendix XI for guidelines 
 
 Extravasation:  
In the event of an extravasation, discontinue the IV 
administration of the drug and institute appropriate measures to 
prevent further extravasation and damage according to 
institutional guidelines. Also, see 
https://cogmembers.org/_files/disc/pharmacy/ExtravasationRefer
ence.pdf  for COG reference. 
 
 
Intrathecal Methotrexate/Triple Intrathecal Therapy 


 
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  Systemic toxicity: 
The dosage for IT methotrexate will not be reduced for systemic 
toxicity (myelosuppression, mucositis, etc.). Instead, leucovorin 
may be used at a dose of 5 mg/m2/dose IV/PO every 6 hours x 2 
doses, beginning 24 hours after the IT therapy has been 
delivered. This may reduce the risk of worsening already existent 
myelosuppression (ANC < 500/µL) or mucositis. Do not 
administer leucovorin solely to prevent myelosuppression.  
 
 Dose modifications following an episode of acute neurotoxicity: 
Neurotoxicity has extremely protean manifestations, ranging 
from transient events, seizures or episodes of acute hemiparesis, 
to severe necrotizing encephalopathies.19-21  
 
The following guidelines are offered for consideration following 
an acute event, but it must be recognized that there are little data 
to support these approaches or any others.  
 
Many acute events, seizures or episodes of transient hemiparesis, 
are temporally related to the administration of intrathecal 
therapy, commonly 9 to 11 days after the IT administration.22  
 
Complete clinical evaluation including imaging of the brain is 
strongly recommended.  
 
For patients who return to their baseline pre-event neurological 
status, clinicians may 
1. Hold the next planned dose of IT therapy, or 
2. Substitute IT cytarabine or IT 
cytarabine/hydrocortisone for 1 dose of IT 
methotrexate, or 
3. Proceed with IT methotrexate and include leucovorin 
rescue at a dose of 5 mg/m2 IV/PO q 6 hrs x 2 doses 
beginning 24 hours after the LP. If the event does not 
recur, resumption of standard therapy should be 
considered for subsequent intrathecal therapy.  
 
For patients who do not return to baseline pre-event neurological 
status or for those with recurrent events, or evidence of 
progressive encephalopathy, additional evaluations may be 
warranted and the treating physician may consider a more 
prolonged or definitive change in therapy upon discussion with 
the Study Chair.  
 
 Hydrocephalus, microcephaly or known abnormality of CSF flow 
precluding intrathecal chemotherapy via lumbar puncture:  
Intraventricular chemotherapy via Ommaya catheter may be 
used in place of intrathecal therapy delivered by LP. 
Intraventricular chemotherapy should be given according to the 
same schedule, but at 50% of the corresponding age-based 


 
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doses that would be given by LP. NOTE: Obstruction to CSF 
flow may be a contraindication to intrathecal and/or 
intraventricular therapy. 
 
 Viral, bacterial, or fungal meningitis:  
Omit until resolved. 
 
 
 Steroids (Prednisone, Prednisolone or Methylprednisolone) 
 
 Hypertension:  
Dose should not be reduced. Sodium restriction and anti-
hypertensives should be employed in an effort to control 
hypertension.  
 
 Hyperglycemia:  
Dose should not be reduced for hyperglycemia.  
 
 Pancreatitis:  
Every effort should be made not to hold any re-induction steroids. 
Do not modify dose for asymptomatic elevations of amylase 
and/or lipase. In extreme circumstances, consider discontinuation 
of steroids, except for stress doses, in the presence of Grade 3 or 
4 pancreatitis.  
 
 Osteonecrosis (ON):  
Do not modify corticosteroid therapy for osteonecrosis (also 
referred to as avascular necrosis) during re-induction.   
 
 Varicella:  
Steroids should be held during active infection except during re-
induction. Do not hold during incubation period following 
exposure in patients with laboratory evidence of immunity or 
patients who received appropriate post-exposure prophylaxis. 
 
 Inability to use oral doses: 
For dexamethasone, substitute the IV preparation mg for mg. For 
prednisone, substitute IV methylprednisolone at 80% of the oral 
prednisone dose. Note that if substituting oral prednisolone for 
prednisone, the doses are the same; prednisone is converted in 
the liver to prednisolone. 
 
 Severe infection:  
Do not hold or discontinue steroids during re-induction without 
serious consideration, as this is a critical period in the treatment 
of ALL. Later in therapy, one may consider holding steroid until 
patient achieves cardiovascular stability, except for “stress 
doses.” 
 
 
 
 
 
 
 


 
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Vincristine 
PLEASE USE “BALIS” SCALE FOR GRADING NEUROPATHY (See text box 
below) 
 
 Severe Neuropathic Pain (Grade 3 or greater):  
Hold dose(s). When symptoms subside, resume at 50% previous 
calculated dose (maximum dose: 1 mg), and then escalate to 
full dose as tolerated. NOTE: neuropathic pain can be severe and 
difficult to treat. However, because vinCRIStine is an important 
component of curative therapy and the majority of neuropathies 
are ultimately reversible, vinCRIStine therapy may be given at 
full dose at investigator discretion. Severe peripheral 
neuropathies, with or without a positive family history might 
suggest the need for a molecular diagnostic evaluation to rule out 
Charcot Marie Tooth Disease (CMT), Type 1A or Hereditary 
neuropathy with liability to pressure palsies. Drugs such as 
gabapentin may be of value. 
 
 Vocal Cord Paralysis:  
Hold dose(s). When symptoms subside, resume at 50% previous 
calculated dose (maximum dose: 1 mg), and then escalate to full 
dose as tolerated. See above for comment on CMT.  
 
 Foot Drop, Paresis:  
(Grade 3 or greater): Consider holding or decreasing dose. These 
toxicities are largely reversible but over months to years. 
Accordingly, holding doses of vinCRIStine and/or lowering the 
dose may not result in rapid resolution of symptoms and may 
compromise cure. See above for comment on CMT. Physical 
therapy may be beneficial to maintain range of motion as well as 
to provide ankle-foot orthotics (AFOs) and other forms of 
support. Drugs such as gabapentin may be of value. 
 
 Jaw Pain:  
Treat with analgesics; do not modify vinCRIStine dose. 
 
 Hyperbilirubinemia23,24:  
 
Direct Bilirubin* 
VinCRIStine Dose Adjustment 
< 3.0 mg/dL 
None (maximum dose: 2 mg) 
3.1- 5.0 mg/dL 
50% of calculated dose (maximum dose: 1 mg) 
5.1-6.0 mg/dL 
25% of calculated dose (maximum dose: 0.5 mg) 
> 6.0 mg/dL 
Withhold dose and administer next scheduled dose if toxicity has 
resolved. Do not make up missed doses 
                           *Refer to Appendix XI for guidelines 
 
 Constipation or ileus (≥ Grade 3) or typhlitis: 
Hold dose(s); institute aggressive regimen to treat constipation if 
present. When symptoms abate resume at 50% of calculated dose 
(maximum dose: 1 mg) and escalate to full dose as tolerated. 
 


 
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 Extravasation: 
In the event of an extravasation, discontinue the IV 
administration of the drug and institute appropriate measures to 
prevent further extravasation and damage according to 
institutional guidelines. Also see 
https://members.childrensoncologygroup.org/_files/disc/Nursing/
extravasationguidelines.pdf for COG reference. 
 
 
 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
 
Concurrent Anticancer Therapy 
Additional cancer therapy, including chemotherapy, radiation therapy, immunotherapy, 
or may NOT be administered to patients receiving protocol therapy. If these treatments 
are administered the patient will be removed from protocol therapy. 
 
 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. See COG Supportive Care Guideline at 
Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies 
 
Peripheral Motor Neuropathy: 
• Grade 1: Subjective weakness, but no deficits detected on neurological exam, other than abnormal 
deep tendon reflexes. 
 
• Grade 2: Weakness that alters fine motor skills (buttoning shirt, coloring, writing or drawing, using 
eating utensils) or gait without abrogating ability to perform these tasks. 
 
• Grade 3: Unable to perform fine motor tasks (buttoning shirt, coloring, writing or drawing, using 
eating utensils) or unable to ambulate without assistance. 
 
• Grade 4: Paralysis. 
 
Peripheral Sensory Neuropathy: 
• Grade 1: Paresthesias, pain, or numbness that do not require treatment or interfere with extremity 
function. 
 
• Grade 2: Paresthesias, pain, or numbness that are controlled by non-narcotic medications (without 
causing loss of function), or alteration of fine motor skills (buttoning shirt, writing or drawing, using 
eating utensils) or gait, without abrogating ability to perform these tasks. 
 
• Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with extremity function 
(gait, fine motor skills as outlined above), or quality of life (loss of sleep, ability to perform normal 
activities severely impaired). 
 
• Grade 4: Complete loss of sensation, or pain that is not controlled by narcotics. 


 
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https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines.  See below 
for recommendations on management of specific toxicities associated with palbociclib. 
 
All patients should receive trimethoprim/sulfamethoxazole (TMP/SMX) at a dose of TMP 
2.5 mg/kg/dose (maximum dose 160 mg/dose) by mouth twice daily on 2 or 3 sequential 
days per week. Patients allergic to or experiencing excessive myelosuppression with 
TMP/SMX can receive prophylaxis per institutional guidelines with alternative agents. 
 
 
Infection Control 
Patients with relapsed ALL have a significant risk of morbidity and mortality 
with intensive salvage therapy. Patients in first relapse have a 4-5% induction 
mortality rate, the majority associated with infection. They have also been found 
to have a 45% rate of Grade 3 and 4 infection during re-induction on recent COG 
ALL trials13 (and personal communication T. Horton, E. Raetz, and M. O’Brien), 
and other relapsed ALL re-induction trials.25-27 Therefore patients with multiply 
relapsed ALL require a very conservative approach to infection prevention and 
treatment as outlined below. 
 
 Due to the substantial risk of infection in patients with relapsed 
ALL receiving intensive induction therapy, it is strongly 
recommended that they remain hospitalized from the initiation of 
therapy until: 1) there is evidence of ANC recovery defined as ≥ 
200/microliter and increasing, and 2) they are afebrile and 
clinically stable.  
 
 It is strongly recommended that patients receive broad spectrum 
gram positive and negative antibiotic prophylaxis at initiation of 
re-induction therapy and until they have met the criteria for 
discharge outlined in Section 7.3.1.1. The specific choice of 
prophylactic antibiotics should be guided by the individual 
institution, although levofloxacin is recommended.28,29 
 
 Prophylactic anti-fungal therapy with IV caspofungin, micafungin 
or amphotericin is also highly recommended.30 The patient should 
remain on prophylactic anti-fungal therapy until their ANC has 
fallen and recovered to 200/microliter and rising and the patient is 
afebrile and clinically stable.   
 
 Empiric broad spectrum antibacterial and anti-fungal therapy 
should be initiated immediately for patients with an ANC < 
500/microliters (or < 1000 /microliters and falling) and an oral 
temperature > 38°C twice in 12 hours or ≥ 38.5°C once or as 
clinically indicated. Broad-spectrum antibiotics and anti-fungals, 
once started, should be continued until there is evidence of ANC 
recovery defined as ≥ 200/microliter.  Also, please see 
the COG Fever and Neutropenia Guidelines at: https://childrenso
ncologygroup.org/index.php/cog-supportive-care-guidelines   
  
 If clinical symptoms or radiographic evidence of enterocolitis or 
typhilitis develop, broad spectrum antibiotics which provide 


 
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coverage for gram negatives, and anaerobes and fungal infections 
is highly recommended. 
 
 When possible during hospitalization it is recommended patients 
be assigned to rooms with special air filtration systems such as 
high efficiency particulate air filters (HEPA) or clean-air rooms 
with constant positive pressure.31 
 
 
Acute Tumor Lysis Syndrome 
Patients with ALL and lymphoblastic lymphoma are at high risk of tumor lysis 
should be assessed rapidly for evidence of symptomatic hyperleukocytosis, tumor 
lysis syndrome, and coagulopathy. Suggested initial studies, obtained prior to 
initiating antileukemia therapy, may include a complete blood count (CBC), 
prothrombin and activated partial thromboplastin times, fibrinogen, D-dimer, and 
serum electrolytes, including creatinine, BUN, uric acid, phosphorus, and calcium. 
Continued monitoring of these studies should be carried out at suitable intervals 
until abnormalities have resolved or the risk has abated. 
The risk for serious acute tumor lysis syndrome (TLS) is usually restricted to the 
first 72 hours after initiation of therapy; however, it may spontaneously occur 
prior to treatment. To manage the metabolic derangements caused by 
hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia, the 
following steps should be initiated: 
• 
Begin allopurinol at a dose of 300 mg/m²/day or 10 mg/kg/day (maximum 
800 mg/day) in 2 - 3 divided doses and continue until peripheral blasts and 
extramedullary disease are reduced. In some patients, such as those with 
oliguria or severe renal dysfunction, or in those with marked hyperuricemia, it 
may be also be appropriate to use rasburicase. Note that rasburicase is 
contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) 
deficiency. 
• 
Hydrate at 2,400-3,000 mL/m²/day to maintain urine output > 100 
mL/m²/hour until peripheral blasts and extramedullary disease are reduced. 
Potassium should not be added to the hydration fluids. 
 
Urine alkalinization is NOT necessary for TLS prophylaxis. There is paucity of 
evidence demonstrating benefit of urine alkalinization and it can potentially lead 
to calcium phosphate precipitation and/or metabolic acidosis. 
 
 
Growth Factors 
Growth factors that support white cell number or function can only be administered 
culture proven bacteremia or invasive fungal infection. The Study Chair should be 
notified before growth factors are initiated. 
 
 
Concomitant Medications 
 
 
Cytochrome P450 and antileukemic drugs 
Since concurrent use of enzyme inducing anticonvulsants (e.g., phenytoin, 
phenobarbital, and carbamazepine) with anti-leukemic therapy has recently been 
associated with inferior EFS, every effort should be made to avoid these agents, 
as well as rifampin, which also induces many drug metabolizing enzymes.24 
Neither gabapentin nor levetiracetam induce hepatic drug metabolizing enzymes 


 
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and may be suitable alternative anticonvulsants. Azole antifungals (listed in the 
table below) and the macrolide group of antibiotics (listed in the table below) 
may have potent inhibitory effects on drug-metabolizing enzymes. Patients 
receiving some anti-leukemic drugs (e.g., vincristine, anthracyclines, etoposide) 
may experience excess toxicity when these agents are given concomitantly; 
alternate antifungal and antibacterial therapy should be used where possible (see 
table below). 
 
DRUGS 
POTENTIAL 
INTERACTION 
ACTION TO BE TAKEN 
Anticonvulsants 
Induction of drug 
metabolizing enzymes 
Lowered EFS 
AVOID phenytoin, phenobarbital, 
carbamazepine 
Consider gabapentin or levetiracetam as 
alternative 
Rifampin 
Induction of drug 
metabolizing enzymes  
DO NOT USE 
Azole Antifungals 
(itraconazole*, 
posaconazole, 
voriconazole, 
ketoconazole, 
isavuconazole) 
Inhibition of drug 
metabolizing enzymes 
CONSIDER ALTERNATIVE 
MEDICATIONS 
May need dose reductions of vincristine*, 
anthracyclines, etoposide, steroids 
Macrolide 
Antibiotics 
(erythromycin, 
clarithromycin, 
azithromycin, 
roxithromycin, 
telithromycin) 
Inhibition of drug 
metabolizing enzymes 
CONSIDER ALTERNATIVE 
MEDICATIONS 
May need dose reductions of vincristine, 
anthracyclines, etoposide, steroids 
  * Itraconazole should NOT be used in patients who are receiving vincristine due to a 
serious drug-drug interaction leading to severe neurotoxicity.32,33 
 
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 Interactions and palbociclib 
In vitro data indicate that CYP3A and sulfotransferase (SULT) enzyme 
SULT2A1 are mainly involved in the metabolism of palbociclib. Palbociclib is a 
strong substrate of CYP3A4 isozyme.  
The concomitant use of strong CYP3A4 inhibitors including, but not limited to 
atazanavir, boceprevir, clarithromycin, itraconazole, ketoconazole, 
lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, ritonavir, 
telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, may 
increase palbociclib plasma concentrations and should be avoided (see Appendix 
III for list of agents).  
The concomitant use of strong CYP3A4 inducers including, but not limited to 
carbamazepine, enzalutamide, felbamate, nevirapine, phenobarbital, phenytoin, 
primidone, rifabutin, rifampin, rifapentin, and St. John’s wort, may decrease 
palbociclib plasma concentrations and should be avoided (see Appendix III for 
list of agents).  


 
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Strong inducers and/or strong inhibitors of CYP3A4 are prohibited from 14 days 
prior to enrollment to the end of the study. See Appendix III for a list of agents. 
The use of moderate inhibitors and/or inducers of CYP3A4 should be avoided as 
well for the duration of the study, if reasonable alternatives exist. 
Palbociclib is a weak time-dependent inhibitor of CYP3A4 in humans. The use 
of sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow 
therapeutic range should be avoided for the duration of the study if reasonable 
alternatives exist (Appendix III).  
  
 


 
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 
days prior to enrollment unless otherwise indicated. Laboratory values used to assess 
eligibility (see Section 4.0) must be no older than seven (7) days at the start of therapy.  
Laboratory tests need not be repeated if therapy starts within seven (7) days of obtaining 
labs to assess eligibility.  If a post-enrollment lab value is outside the limits of eligibility, 
or laboratory values are older than 7 days, then the following laboratory evaluations must 
be re-checked within 48 hours prior to initiating therapy: bilirubin, ALT (SGPT) and 
serum  creatinine.  If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies, 
bone marrow aspirate and/or biopsy, must be obtained within 14 days prior to start of 
protocol therapy (repeat the tumor imaging if necessary). 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
End of Protocol 
Therapy- Day 32^ 
History 
X 
Weekly 
 
Physical exam with vital signs 
X 
Weekly 
X 
Height, weight, BSA 
X 
 
X 
Performance status 
X 
 
X 
Pregnancy test1 
X 
 
 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 days)3 
X 
CSF cell count & cytospin 
X* 
With each IT 
 
Pharmacokinetics2 
X 
X 
 
Urinalysis 
X 
 
 
Electrolytes including Ca++ 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Direct Bilirubin 
X12 
 
 
Albumin 
X 
 
 
ECHO or gated radionuclide study 
X 
 
X  
12-lead EKG 
X 
 
X  
Chest x-ray 
X 
 
 
Patient Diary11 
 
Weekly 
X 
 
ADDITIONAL STUDIES: ALL ONLY 
Bone marrow aspirate for morphology 
and MRD 
X 
 
X4  
Absolute Blast Count (ABC) 
 
Day 45 
 
Correlative biology studies 6 
X 
Day 4 
X 
 
ADDITIONAL STUDIES: LL ONLY  
Chest7 and neck CT 
X 
 
X7,8 
Abdomen/Pelvis CT or MRI 
X 
      
X8 
Chest x-ray 
X 
 
 
PET scan (recommended) 
 X 
 
X 
Bone scan9 
  X9 
 
X9 
Bilateral bone marrow aspirates and 
biopsies for morphology 
X  
 
Only if positive at 
diagnosis10  


 
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^  
Abnormal laboratory tests must be re-checked by Day 42 since some toxicities require resolutions to ≤ 
Grade 2 or baseline by Day 42 (see DLT criteria). 
* 
May be done with the Day 1 lumbar puncture with IT therapy.  
1 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 
active patients must use an acceptable method of birth control.  Abstinence is an acceptable method of 
birth control. 
2 
See Section 8.2 for timing of PK studies. 
3 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until 
recovery to Grade 3. 
4 
Bone marrow aspirate must be obtained on Day 32 + 2 days. MRD should be obtained with this end of 
cycle bone marrow if patient < 5% blasts by morphology. If peripheral blood count recovery is delayed 
at the end of the cycle, repeat a bone marrow aspirate just prior to or on Day 42 regardless of counts. If 
still delayed repeat a bone marrow every 7-14 days after Day 42 until count recovery or relapse.  
5 
Absolute blast count should be performed on Day 4 prior to administration of chemotherapy. 
6 
See Section 8.3 for timing of Correlative Biology studies (optional). Peripheral blood samples should 
be collected PRIOR to administration of Day 4 chemotherapy, if   absolute blast count is >1000/mm3. 
7 
Obtain chest CT for all LL patients at baseline and on Day 32. The baseline chest CT may be delayed 
until the patient is stable. A PET-CT can be used instead of a CT (See Section 12.4). 
8  
If imaging studies are negative at baseline, no further imaging is needed on Day 32. A PET-CT can 
be used instead of a CT (See Section 12.4). 
9 
Bone scan as clinically indicated; perform at Day 32 only if patient has disease at baseline. May 
substitute a PET scan for a bone scan, however, a bone scan is preferred for bone symptoms. 
10 
LL should have bone marrow aspirates and biopsies on Day 32 + 2 days if ≥ 5% marrow 
involvement was present at diagnosis  
11 
Patient diary (see Appendix XII) should be reviewed after completion of each treatment cycle and 
uploaded into RAVE. The patient diary should be collected and reviewed weekly during Cycle 1. 
12      Collect direct bilirubin before start of protocol therapy and as clinically indicated. 
 
 
Pharmacology (required) 
 
 
Description of Studies and Assay 
Palbociclib PK studies will be determined by a validated LC-MS/MS method. 
 
 
Sampling Schedule (See Appendix VIII) 
Plasma samples will be obtained at the following time points: 
• 
Day 1 of Cycle 1: pre-dose, and at 1, 2, 4, 8 and 24 hours post-dose of 
palbociclib.  
• 
Day 11 of Cycle 1: pre-dose, and at 1, 2 and 4, 8 and 24 hours post-dose 
of palbociclib. 
 
 
Sample Collection and Handling Instructions 
Blood samples (3-4 mL) to provide a minimum of 1.0 mL of plasma for PK 
analysis of palbociclib will be collected in tubes containing dipotassium 
ethylenediaminetetraacetic acid (K2EDTA). Record the exact time that the 
sample is drawn along with the exact time that the drug is administered. 
  
 
Sample Processing 
Upon collection of the blood PK samples, keep the samples on wet ice at all 
times prior to processing to plasma.  
• 
The blood samples have to be processed to plasma and placed in a 
freezer at -20ºC within 1 hour of collection.  


 
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• 
To process the blood samples to plasma, centrifuge the blood samples in 
a refrigerated centrifuge at approximately 4 ºC at about 1700 x g for 
approximately 10 minutes.  
• 
Using a clean separate pipette for each time point, transfer the plasma 
samples into pre-labeled 4 or 5 mL polypropylene cryovials and store in 
the freezer at approximately -20ºC until shipment. If a -20ºC freezer is 
not available at the site the samples may be stored at -80ºC. Palbociclib 
is stable at -20ºC and -80ºC for 439 days in frozen K2EDTA plasma.  
• 
Ship the frozen samples on dry ice to the contract bioanalytical 
laboratory.  
 
 
Sample Labeling 
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 Pharmacokinetic Study Form (Appendix VIII), which must accompany the 
sample(s). 
 
 
Sample Shipping Instructions 
A phone call or fax communication should precede all sample shipments. A 
phone or fax communication must precede all HIV positive or other known 
infectious sample shipments.  
 
Detailed sample inventory information (Appendix VIII) must accompany the 
samples. Lack of paperwork or illegible information will delay sample login and 
analysis. Samples that are unclearly or incompletely labeled may also lead to 
delayed analysis. 
 
Samples should be batched and shipped via overnight courier at the end of each 
cycle on Mondays, Tuesdays, or Wednesdays. Samples should be shipped to the 
following address:  
 
 
  
 
 
 
 
 
Correlative Biology Studies (Optional) 
 
 
Description of Studies 
Correlative biology studies in bone marrow and peripheral blood will be 
performed in consenting patients to determine the biological activity of CDK4/6 
inhibition. RNA sequencing and Western blotting will be used to determine gene 
and protein expression.  Cell cycle analyses will be performed to determine the 
percentage of S phase cells prior to and after palbociclib exposure. 
 
 
Sampling Schedule (See Appendix II) 
One bone marrow or blood sample (10-15mL) for each time point will be 
collected to assess for the studies outlined below. Peripheral blood also can be 


 
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substituted or used to augment bone marrow samples if the absolute blast count is 
>1000/μL: 10 mL per samples (<10 kg) or 15 mL (≥10 kg).   
 
 
Pre-study 
Marrow 
Day 4 
Blood 
Day 32* 
Marrow 
Targeted DNA 
sequencing to identify 
somatic mutations in both 
T-ALL and B-ALL 
samples 
 
 
X 
 
 
CDKN2A deletions 
(using FISH) 
X 
 
 
RB1 expression and RB1 
phosphorylation status 
(Immunoblotting) 
X 
X** 
X 
p27Kip1 expression 
(Immunoblotting) 
X 
X** 
X 
Cyclin D3 and CDK4/6 
protein expression 
(Immunoblotting) 
X 
X** 
X 
Cell cycle analysis 
(response to Palbociclib) 
X 
X** 
X 
Peripheral blood absolute 
blast count 
X 
X** 
 
* End of therapy analyses in patients with persistent disease. End of therapy analyses must be obtained on Day 
32 + 2 days.  
** Peripheral blood samples should be collected PRIOR to administration of Day 4 chemotherapy, if   absolute 
blast count is >1000/mm3  
 
 
Sample Collection and Handling Instructions 
Bone marrow 5mL per sample or peripheral blood**: 10 mL per samples (<10 
kg) or 15 mL (≥ 10 kg) if absolute blast count is >1000/mm3.   
 
 
Sample Processing (See Appendix II for details) 
Lymphoblasts will be isolated from bone marrow or blood within 4 hours of 
collection using Ficoll-Paque Plus (Amersham Biosciences, Brown Deer, WI) at 
participating centers to avoid potential artifacts associated with prolonged sample 
storage or shipping.  Blasts will then be frozen and batch shipped on dry ice to 
the Carroll/Aifantis labs for DNA and protein purification (per Section 
8.3.6). Email or call Nikki Evensen, PhD (Nikki.Evensen@nyulangone.org; 
(212) 263-2327 or (516) 765-6832) for any questions regarding sample 
processing.  
 
 
Sample Labeling 
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 Correlative Study Form (Appendix IX), which must accompany the 
sample(s). 
 
 
Sample Shipping Instructions 
Samples should be batched per patient and shipped frozen on dry ice to arrive 
Monday-Friday. Do not ship samples for delivery on a weekend or holiday. 
 


 
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Ship samples to: 
 
Carroll/Aifantis Labs 
   Laura and Isaac Perlmutter Cancer Center at NYU Langone 
522 First Avenue, Smilow Building 12 Floor, Room 1211 
Tel: 212.263.2327 • Fax: 212.263.9190  
New York, NY 10016   
 
 
 
 
 
 
Ship samples by FedEx using Carroll/Aifantis Labs FedEx account number: 
320569834. 
9.0 
AGENT INFORMATION 
 
 
Palbociclib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 


 
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• 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 


 
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 Toxicities 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Palbociclib (PD-0332991, NSC 772256) 
 
The Comprehensive Adverse Event 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. 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 1751 patients. 
Below is the CAEPR for Palbociclib (PD-0332991). 
 
Version 2.4, September 13, 20191 
 
Adverse Events with Possible 
Relationship to Palbociclib (PD-0332991) 
(CTCAE 5.0 Term) 
[n= 1751] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
 
 
 
Febrile neutropenia 
 
EYE DISORDERS 
 
 
Blurred vision 
 
 
 
Dry eye 
 
 
 
Watering eyes 
 
 
GASTROINTESTINAL DISORDERS 
 
 
Constipation 
 
 
 
Diarrhea 
 
 
 
Mucositis oral 
 
 
Nausea 
 
 
 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Fatigue 
 
 
 
 
Fever 
 
 
INFECTIONS AND INFESTATIONS 
 
Infection2 
 
 
 
INVESTIGATIONS 
 
 
Alanine aminotransferase 
increased 
 
 
 
Aspartate aminotransferase 
increased 
 
 
 
Lymphocyte count decreased 
 
 
Neutrophil count decreased 
 
 
 
 
Platelet count decreased 
 
 


 
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Adverse Events with Possible 
Relationship to Palbociclib (PD-0332991) 
(CTCAE 5.0 Term) 
[n= 1751] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
White blood cell decreased 
 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dysgeusia 
 
 
 
Headache3 
 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Epistaxis 
 
 
 
 
Pneumonitis 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
 
 
Dry skin 
 
 
 
Skin and subcutaneous tissue 
disorders - Other (rash)4  
 
 
 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  
 
2 Infection includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
3Headache has been observed in trials using Palbociclib (PD-0332991) in combination with fulvestrant. 
 
4 Rash includes rash, rash maculo-papular, erythema, erythematous rash, erysipelas, rash pruritic, rash papular, 
generalized rash, exanthema, allergic dermatitis, dermatitis acneiform, dermatitis. 
 
5 Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory neuropathy under the 
NERVOUS SYSTEM DISORDERS SOC. 
 
Adverse events reported on Palbociclib (PD-0332991) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Palbociclib (PD-0332991) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Blood and lymphatic system 
disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Cardiac disorders - Other (paroxysmal atrial 
fibrillation with rapid ventricular response); Palpitations; Pericarditis; Sinus bradycardia; Supraventricular 
tachycardia 
EYE DISORDERS - Cataract; Eye disorders - Other (retinal hemorrhage) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Ascites; Colitis; Colonic 
perforation; Dry mouth; Dyspepsia; Dysphagia; Esophageal stenosis; Flatulence; Gastric hemorrhage; 
Gastrointestinal disorders - Other (gastrointestinal hemorrhage); Intra-abdominal hemorrhage; Lower 
gastrointestinal hemorrhage; Small intestinal obstruction; Small intestinal perforation; Upper gastrointestinal 
hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema limbs; 
Localized edema; Malaise; Non-cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (bile duct obstruction); 
Hepatobiliary disorders - Other (jaundice) 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Fracture 


 
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INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; Creatinine 
increased; Ejection fraction decreased; GGT increased; INR increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypermagnesemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; 
Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Flank pain; 
Generalized muscle weakness; Muscle cramp; Musculoskeletal and connective tissue disorder - Other 
(osteomyelitis); Myalgia; Neck pain; Osteonecrosis; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL. CYSTS AND POLYPS) - Treatment 
related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Dysphasia; Intracranial hemorrhage; Nervous 
system disorders - Other (peripheral neuropathy)5; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Psychiatric disorders - Other (altered mental status) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Hypoxia; 
Oropharyngeal pain; Pleural effusion; Postnasal drip; Pulmonary edema; Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Pruritus 
VASCULAR DISORDERS - Hypertension; Hypotension 
 
Note: Palbociclib (PD-0332991) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 Agent Accountability 
Accountability for the study drug at the trial site is the responsibility of the 
investigator.  The investigator will ensure that the study drug is used only in 
accordance with this protocol. Where allowed, the investigator may choose to 
assign some of the drug accountability responsibilities to a pharmacist or other 
appropriate individual. The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents using the appropriate NCI Investigational Agent (Drug) 
Accountability Record (DARF) for oral agents available on the CTEP forms 
page. Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. Before destroying any unused inventory, site should contact the COG 
Operations Center to confirm that it should not instead be returned to Pfizer. 
These records will adequately document that the patients were provided the doses 
as specified in the protocol and should reconcile all palbociclib received from 
Pfizer. Accountability records will include dates, quantities, batch/serial 
numbers, expiration dates (if applicable), and patient numbers.  
 
All opened (i.e. aluminum overseal broken) bottles (full, partially used, and 
empty) may be destroyed at the site by the appropriate site personnel (e.g. 
Pharmacist; Study Nurse/Coordinator) following local environmental 
requirements and institutional policies. Discarded volumes of palbociclib 
solutions must be disposed of as hazardous waste according to local site 
procedures. Other items used in the dose preparation and administration must be 
disposed of according to local site procedures.  
 
All unused or expired palbociclib will be returned to Pfizer or if authorized, 
disposed of at the study site and documented. All material containing palbociclib 
will be treated and disposed of as hazardous waste in accordance with governing 
regulations. 


 
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 Obtaining the Agent 
Palbociclib will be supplied by Pfizer. Only use palbociclib provided for 
investigational use specifically for AINV18P1.  
 
Palbociclib can be obtained by following the instructions on the agent request 
form provided on the AINV18P1 protocol page of the COG website 
(https://members.childrensoncologygroup.org/). 
 
The drug supply must be stored in a locked limited access area. Palbociclib is for 
investigational use only, and is to be used only within the context of this study. 
Under no circumstances should the investigator or other site personnel supply 
study drug to other investigators, subjects, or clinics, or allow supplies to be used 
other than directed by this protocol. 
 
 
Cytarabine 
 
 
 
 
 
 
 
(07/13/15) 
(Cytosine arabinoside, Ara-C, Cytosar®) NSC #63878 
 
 
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 administration. Intrathecally 
administered doses are metabolized and eliminated more slowly with a t½ of 
about 2 hours. 
 
Intrathecal Therapy (Cytarabine Single Agent) 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 
 
Arachnoiditis 
Rash, somnolence, 
meningismus, convulsions, 
paresis 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
 
Myelosuppression, ataxia 
Delayed: 
Any time later during 
therapy, excluding the 
above condition 
 
 
Necrotizing 
leukoencephalopathy, 
paraplegia, blindness (in 
combination with XRT & 
systemic therapy) 


 
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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 Modification sections of the protocol. 
 
Intrathecal: 
For intrathecal administration, dilute with 5-10 mL (or volume per institutional 
practice) preservative free 0.9% sodium chloride injection, lactated Ringer’s 
injection, Elliot’s B solution. The volume of CSF removed should be equal to at 
least ½ the volume delivered. 
 
Patient Age 
(years) 
Recommended 
volume 
10% CSF volume 
CSF Volume * 
1 – 1.99 
5 – 10 mL 
5 mL 
50 + 10 mL (babies) 
2 – 2.99 
5 – 10 mL 
8 mL 
80 + 20 mL (younger children) 
3 – 8.99 
5 – 10 mL 
10 mL 
100 + 20 mL (older children) 
9 or greater 
5 – 10 mL 
13 mL 
130 + 30 mL (adults) 
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 
1962 Dec 20; 267:1273-8 
 
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. 
 
Intrathecal cytarabine mixed in NS, lactated Ringer’s injection, or Elliot’s B 
solution is stable for 24 hours at 25ºC but contains no preservative and should be 
administered as soon as possible after preparation. 
 
 
Supplier: 
Commercially available from various manufacturers. See package insert for further 
information. 
 
 
Methotrexate  
 
 
 
 
 
 
(05/07/19) 
(MTX, amethopterin, Trexall®, Xatmep®) 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 


 
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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. After oral 
administration, approximately 60% of a 30 mg/m2 dose is rapidly absorbed from 
the GI tract, with peak blood levels at 1 hour. At doses > 30 mg/m² absorption 
decreases significantly. Even at low doses absorption may be very erratic, varying 
between 23% and 95%. The elimination of MTX from the CSF after an intrathecal 
dose is characterized by a biphasic curve with half-lives of 4.5 and 14 hours. After 
intrathecal administration of 12 mg/m², the lumbar concentration of MTX is 
~100 times higher than in plasma. (Ventricular concentration is ~ 10% of lumbar 
concentration). 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. 
 
Intrathecal Therapy (Methotrexate Single Agent) 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, headache 
Arachnoditis: (headache, 
fever, vomiting, 
meningismus, nuchal 
rigidity, and pleocytosis) 
Anaphylaxis, vomiting, seizures(L), 
malaise, confusion, back pain, rash, 
bleeding into subarachnoid or 
subdural space (risk > with platelet 
counts < 20,000), 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
 
 
Myelosuppression, ataxia, 
somnolence, cranial nerve palsy, 
subacute myelopathy 
(paraparesis/paraplegia), speech 
disorders, pain in the legs, bladder 
dysfunction 
Delayed: 
Any time later during 
therapy, excluding the 
above condition 
 
Cognitive disturbances 
(L)1, 
learning disability (L)1 
 
 
Leukoencephalopathy1 (L) 
Late: 
Any time after the 
completion of treatment 
 
 
Progressive CNS deterioration1 
1 May be enhanced by HDMTX and/or cranial irradiation. 
(L) Toxicity may also occur later. 
 
 
Formulation & 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 


 
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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.  
 
For Intrathecal use: Use preservative free 25 mg/mL solution. 
 
For intrathecal administration, dilute with 5-10 mL preservative free NS, lactated Ringer’s, 
or Elliot’s B solution as per institutional standard of practice. The volume of CSF removed 
should be equal to at least half the volume delivered. 
 
 
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 
1962 Dec 20; 267:1273-8 
 
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. 
 
Diluted methotrexate for intrathecal administration is stable for 24 hours at 25ºC but 
contains no preservative and should be administered as soon as possible after preparation. 
 
 
Supplier: 
Commercially available from various manufacturers. See package insert for further 
information. 
 
 
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 
Patient Age 
(years) 
Methotrexate 
dose 
Recommended volume 
10% CSF volume 
CSF Volume * 
1–1.99 
8 mg 
5–10 mL 
5 mL 
50 + 10 mL 
(babies) 
2–2.99 
10 mg 
5-10 mL 
8 mL 
80 + 20 mL 
(younger children) 
3–8.99 
12 mg 
5-10 mL 
10 mL 
100 + 20 mL 
(older children) 
9 or greater 
15 mg 
5-10 mL 
13 mL 
130 + 30 mL 
(adults) 


 
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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) 
Demyelinating 
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. 
 
 
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. 
 
Patient Age 
(years) 
Doses 
(MTX/Hydrocortisone/Ara-C) 
 
Recommended 
volume 
10% CSF 
volume 
CSF Volume * 
0 – 0.99 
7.5 mg / 7.5 mg / 15 mg 
5-10 mL 
5 mL 
50 + 10 mL  
(babies) 
1 – 1.99 
8 mg / 8 mg / 16 mg 
5-10 mL 
5 mL 
50 + 10 mL  
(babies) 
2 – 2.99 
10 mg / 10 mg / 20 mg 
5-10 mL 
8 mL 
80 + 20 mL  


 
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*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection. N Engl J Med 
1962 Dec 20; 267:1273-8 
 
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. 
 
Intrathecal triples are stable in NS for 24 hours at 25ºC but contain no preservative and 
should be administered as soon as possible after preparation. 
 
 
Supplier: 
Commercially available from various manufacturers. See package insert for further 
information. 
 
 
Doxorubicin 
 
 
 
 
 
 
 
(05/09/11) 
(Adriamycin®) NSC #123127  
 
 
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, 
(younger children) 
3 – 8.99 
12 mg / 12 mg / 24 mg 
5-10 mL 
10 mL 
100 + 20 mL  
(older children) 
9 or greater 
15 mg / 15 mg / 30 mg 
5-10 mL 
13 mL 
130 + 30 mL  
(adults) 


 
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doxorubicinol, to plasma proteins is about 74 to 76% and is independent of 
plasma concentration of doxorubicin. 
 
 
 Doxorubicin 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 mg¹ vials 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, 


 
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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. 
 
 
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. 
 
 
PREDNISO(LO)NE 
 
 
 
 
 
(11/16/17) 
(Deltasone®, PredniSONE Intensol®, Rayos®, Meticorten®, Liquid Pred®, Pediapred®, 
Millipred®, OraPred ODT®) NSC #10023 (prednisone), NSC# 9151 (prednisolone) 
 
 
Source and Pharmacology: 
Prednisone and prednisolone are a synthetic compounds closely related to 
hydrocortisone. 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. Peak blood levels occur within 2 hours of oral intake. Prednisone 
is approximately 75% protein bound with a plasma t½ of 3.2 to 4 hours. (Biologic 
half-life is 12- 36 hours.)  
 
PREDNISO(LO)NE 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), electrolyte 
imbalance (Na retention, 
hypokalemia, hypocalcemia) (L), 
increased intraocular pressure (L), 
hypertension, psychosis, vertigo, 
headache 
Delayed: 
Cushing’s syndrome (moon 
facies, truncal obesity) 
Striae and thinning of the 
skin, easy bruising, 
Spontaneous fractures (L), growth 
suppression, peptic ulcer and GI 


 
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Any time later 
during therapy 
muscle weakness, 
osteopenia  
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 
prednisone in children) 
 
Unknown 
Frequency and 
Timing:  
Fetal and teratogenic toxicities: Corticosteroids cross the placenta (prednisone has the 
poorest transport). 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. Prednisone is 
excreted into breast milk in humans; however, several studies suggest that amounts excreted 
in breast milk are negligible with prednisone doses ≤ 20 mg/day.  
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: 
Prednisone is available in 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, and 50 mg tablets. 
Also available as a solution in 1 mg/1 mL or 5 mg/mL concentrations. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include 
calcium or magnesium stearate, corn starch, lactose, erythrosine sodium, mineral 
oil, sorbic acid, sucrose, talc and various dyes. The solution may include 5-30% 
alcohol, fructose, sucrose, saccharin, and sorbitol. 
 
Prednisolone is available as 5 mg scored tablets (base) and 10 mg, 15 mg, and 
30 mg orally disintegrating tablets (ODT; sodium phosphate [strength expressed 
as base]). Liquid formulations of prednisolone are available as 15 mg/5 mL oral 
solution (base); 5 mg/5 mL, 10 mg/5 mL, 15 mg/5 mL, 20 mg/5 mL oral solution 
(sodium phosphate [strength expressed as base]; and 15 mg/5 mL oral syrup 
(base). Inactive ingredients vary depending on manufacturer. Tablet formulations 
may contain dyes and liquid formulations may contain edetate disodium, 
methylparaben, saccharin sodium.  
 
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of the protocol. 
 
PredniSONE and prednisoLONE are equipotent corticosteroids. 
 
 
Supplier: 
Commercially available from various sources. See package insert for further 
information. 
 
 
Vincristine  
 
 
 
 
 
 
 
(08/16/12) 
(Oncovin®, VCR, LCR) NSC #67574 
 
 
Source and Pharmacology: 
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to 
tubulin, disrupting microtubules and inducing metaphase arrest. Its serum decay 
pattern is triphasic. The initial, middle, and terminal half-lives are 5 minutes, 


 
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2.3 hours, and 85 hours respectively; however, the range of the terminal half-life 
in humans is from 19 to 155 hours. The liver is the major excretory organ in 
humans and animals; about 80% of an injected dose of vincristine sulfate appears 
in the feces and 10% to 20% can be found in the urine. The p450 cytochrome 
involved with vincristine metabolism is CYP3A4. Within 15 to 30 minutes after 
injection, over 90% of the drug is distributed from the blood into tissue, where it 
remains tightly, but not irreversibly bound. It is excreted in the bile and feces. 
There is poor CSF penetration.  
 
 
Vincristine 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 
 
Jaw pain, headache 
Extravasation (rare) but if occurs = 
local ulceration, shortness of breath, 
and bronchospasm 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
Alopecia, constipation 
Weakness, abdominal 
pain, mild brief 
myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia) 
Paralytic ileus, ptosis, diplopia, 
night blindness, hoarseness, vocal 
cord paralysis, SIADH, seizure, 
defective sweating 
Delayed: 
Any time later during 
therapy 
Loss of deep tendon reflexes 
Peripheral paresthesias 
including numbness, 
tingling and pain; 
clumsiness; wrist drop, 
foot drop, abnormal gait  
Difficulty walking or inability to 
walk; sinusoidal obstruction 
syndrome (SOS, formerly VOD) (in 
combination); blindness, optic 
atrophy; urinary tract disorders 
(including bladder atony, dysuria, 
polyuria, nocturia, and urinary 
retention); autonomic neuropathy 
with postural hypotension; 8th 
cranial nerve damage with 
dizziness, nystagmus, vertigo and 
hearing loss 
Unknown Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of vincristine (either alone or in combination with 
other antineoplastic agents) have been noted in humans. The toxicities include: 
chromosome abnormalities, malformation, pancytopenia, and low birth weight. It is 
unknown whether the drug is excreted in breast milk. 
 
 
Formulation and Stability: 
Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains 
vincristine sulfate 1 mg (1.08 µmol), mannitol 100 mg, SWFI; acetic acid and 
sodium acetate are added for pH control. The pH of vincristine sulfate injection, 
USP ranges from 3.5 to 5.5. This product is a sterile, preservative free solution. 
Store refrigerated at 2˚-8˚C or 36˚-46˚F. Protect from light and retain in carton 
until time of use. 
 
Do not mix with any IV solutions other than those containing dextrose or saline. 
 
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of protocol. 
 
The World Health Organization, the Institute of Safe Medicine Practices (United 
States) and the Safety and Quality Council (Australia) all support the use of 


 
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minibag rather than syringe for the infusion of vincristine. The delivery of 
vincristine via either IV slow push or minibag is acceptable for COG protocols. 
Vincristine should NOT be delivered to the patient at the same time with any 
medications intended for central nervous system administration. Vincristine is 
fatal if given intrathecally. 
 
Injection of vincristine sulfate should be accomplished as per institutional policy. 
Vincristine sulfate must be administered via an intact, free-flowing intravenous 
needle or catheter. Care should be taken to ensure that the needle or catheter is 
securely within the vein to avoid extravasation during administration. The 
solution may be injected either directly into a vein or into the tubing of a running 
intravenous infusion. 
 
Special precautions: 
FOR INTRAVENOUS USE ONLY. 
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement: “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.” 
 
 
Supplier: 
Commercially available from various manufacturers. See package insert for more 
detailed information. 
 
 
Pegaspargase   
 
 
 
 
 
(06/05/17) 
(PEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene glycol-L-asparaginase, 
Oncaspar®) NSC #624239 
 
 
Source and Pharmacology: 
Pegaspargase is a modified version of the enzyme L-asparaginase. L-asparaginase 
is modified by covalently conjugating units of monomethoxypolyethylene glycol 
(PEG), molecular weight of 5000, to the enzyme, forming the active ingredient 
PEG-L-asparaginase. The L-asparaginase (L-asparagine amidohydrolase, type 
EC-2, EC 3.5.1.1) used in the manufacture of Pegaspargase is derived from 
Escherichia coli which is purchased in bulk from Merck, Sharp and Dohme. L-
asparagine is a nonessential amino acid synthesized by the transamination of L-
aspartic acid by a reaction catalyzed by the enzyme L-asparagine synthetase. The 
ability to synthesize asparagine is notably lacking in malignancies of lymphoid 
origin. Asparaginase depletes L-asparagine from leukemic cells (especially 
lymphoblasts) by catalyzing the conversion of L-asparagine to aspartic acid and 
ammonia. In predominately L-asparaginase naive adult patients with leukemia and 
lymphoma, initial plasma levels of L-asparaginase following intravenous 
administration of pegaspargase were determined. Apparent volume of distribution 
was equal to estimated plasma volume. L-asparaginase was measurable for at least 
15 days following the initial treatment with Pegaspargase. The approximate t½ in 
adult patients is 5.73 days. The enzyme could not be detected in the urine. The half-
life is independent of the dose administered, disease status, renal or hepatic 
function, age, or gender. In a study of newly diagnosed pediatric patients with ALL 
who received either a single intramuscular injection of pegaspargase (2500 IU/m2), 
E. coli L-asparaginase (25000 IU/m2), or Erwinia (25000 IU/m2), the plasma half-
lives for the three forms of L-asparaginase were: 5.73 ± 3.24 days, 


 
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1.24 ± 0.17 days, and 0.65 ± 0.13 days respectively. The plasma half-life of 
pegaspargase is shortened in patients who are previously hypersensitive to native 
L-asparaginase as compared to non-hypersensitive patients. L-asparaginase is 
cleared by the reticuloendothelial system and very little is excreted in the urine or 
bile. Cerebrospinal fluid levels are < 1% of plasma levels. 
 
 
Pegaspargase 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 
Allergic reactions (total 
likelihood of local, and or 
systemic reaction especially 
if previous hypersensitivity 
reaction to native 
asparaginase), pain at 
injection site, weakness, 
fatigue, diarrhea  
Allergic reactions (total 
likelihood of local, and 
or systemic reaction if 
no previous 
hypersensitivity 
reaction to native 
asparaginase), rash  
Anaphylaxis, hyper/hypotension, 
tachycardia, periorbital edema, 
chills, fever, dizziness, dyspnea, 
bronchospasm, lip edema, 
arthralgia, myalgia, urticaria, mild 
nausea/vomiting, abdominal pain, 
flatulence, somnolence, lethargy, 
headache, seizures (L), 
hyperuricemia  
Prompt: 
Within 2-
3 weeks, prior to 
the next course 
Hyperammonemia (L), 
coagulation abnormalities 
with prolonged PTT, PT and 
bleeding times (secondary 
to decreased synthesis of 
fibrinogen, AT-III & other 
clotting factors) (L) 
Hyperglycemia, 
abnormal liver function 
tests, pancreatitis (L), 
increased serum 
lipase/amylase 
Hemorrhage (L), DIC, thrombosis, 
anorexia, weight loss, CNS 
ischemic attacks, edema, azotemia 
and decreased renal function, mild 
leukopenia, granulocytopenia, 
thrombocytopenia, pancytopenia, 
hemolytic anemia, infections (sepsis 
with/without septic shock, subacute 
bacterial endocarditis [SBE], URI), 
CNS changes including irritability, 
depression, confusion, EEG 
changes, hallucinations, coma and 
stupor, paresthesias, 
hypertriglyceridemia, 
hyperlipidemia, Parkinson-like 
syndrome with tremor and increase 
in muscular tone, 
hyperbilirubinemia, chest pain  
Delayed: 
Any time later 
during therapy 
 
 
Renal failure, urinary frequency, 
hemorrhagic cystitis, elevated 
creatinine and BUN, fatty liver 
deposits, hepatomegaly, liver failure 
Unknown 
Frequency and 
Timing:  
Animal reproduction studies have not been conducted with pegaspargase. It is not known 
whether pegaspargase can cause fetal harm when administered to a pregnant woman or can 
affect reproduction capacity. However, fetal toxicities and teratogenic effects of asparaginase 
have been noted in animals. It is unknown whether the drug is excreted in breast milk. 
(L)Toxicity may also occur later. 
 
 
Formulation and Stability: 
Each milliliter of pegaspargase contains: PEG-L-asparaginase 750 IU ± 20%, 
monobasic sodium phosphate, USP 1.20 mg ± 5% dibasic sodium phosphate, USP 
5.58 mg ± 5%, sodium chloride, USP 8.50 mg ± 5% , Water for Injection, USP qs 
to 1 mL. The specific activity of pegaspargase is at least 85 IU per milligram 
protein. Available in 5 mL vials as Sterile Solution for Injection in ready to use 
single-use vials, preservative free. Keep refrigerated at 2°-8°C (36°-46°F). Do not 


 
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use if stored at room temperature for more than 48 hours. DO NOT FREEZE. Do 
not use product if it is known to have been frozen. Freezing destroys activity, 
which cannot be detected visually.  
 
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of the protocol. 
 
For IM administration: the volume at a single injection site should be limited to 
2 mL. If the volume to be administered is greater than 2 mL, multiple injection 
sites should be used.  
 
For IV administration: dilute pegaspargase in 100 mL of NS or D5W and infuse 
over 1 to 2 hours through a NS or D5W running infusion line. Pegaspargase 
admixed in 100 mL of NS or D5W is stable for 48 hours at room temperature. 
Pegaspargase diluted in 100 mL of NS is stable for up to 72 hours refrigerated (4ºC 
[39°F]) (refrigerated stability data on file with Sigma-Tau). Avoid excessive 
agitation. DO NOT SHAKE. Do not use if cloudy of if precipitate is present.  
 
Have available during and after the infusion: antihistamine, epinephrine, oxygen, 
and IV corticosteroids. Observe patient for ONE hour after administration for signs 
of hypersensitivity reactions. 
 
 
Supplier: 
Commercially available. See package insert for further information. 
 
 
Asparaginase Erwinia Chrysanthemi 
 
(05/07/19) 
(Erwinia Chrysanthemi, Erwinase®, Erwinazetm, Crisantaspase) NSC #106977 
 
 
Source and Pharmacology: 
L-asparagine is a nonessential amino acid synthesized by the transamination of 
L-aspartic acid by a reaction catalyzed by the enzyme L-asparagine synthetase. 
Neoplastic cells associated with acute lymphoblastic leukemia, acute myeloid 
leukemia and lymphoblastic lymphosarcoma are asparagine-dependent but lack 
asparagine synthetase activity. The administration of L-asparaginase produces an 
anti-neoplastic effect by catalyzing asparagine into aspartic acid and ammonia. 
As a result, these cells lack the ability to produce the asparagine necessary for 
protein metabolism and survival. Deamination of glutamine may also play a role 
in the antineoplastic activity of asparaginase. 
 
Asparaginase Erwinia chrysanthemi (Erwinaze) is asparaginase derived from 
cultures of Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme; each of 
the four identical subunits has a molecular weight of approximately 35 kDa. 
Asparaginase Erwinia chrysanthemi is immunologically distinct from E.coli L-
asparaginase and may allow continued asparaginase therapy when a 
hypersensitivity reaction occurs to Escherichia coli-derived asparaginase. The 
package labeling states that there is insufficient information to characterize the 
incidence of antibodies to asparaginase Erwinia chrysanthemi. Several factors are 
involved in immunogenicity assay results and the assessment of antibodies, 
including assay methodology, assay sensitivity and specificity, sample handling, 
timing of sample collection, concomitant medications, and the underlying disease 


 
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state. The following data have been reported on each of the three preparations of 
asparaginase: 
 
Clinical Pharmacology of 
Asparaginase 
Formulation 
Elimination half-life (IM) 
% Anti-Asparaginase Antibody 
positive patients 
Native Escherichia Coli 
26-30 hours 
45-75 
Pegylated-asparaginase 
5.5-7 days 
5-18 
Erwinia Asparaginase 
16 hours (7-13 hrs package insert) 
30-50 
From: Avramis, V; Panosyan, E; Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase Formulations: 
The Past, the Present and Recommendations for the Future. Clin Pharmacokinet 2005; 44 (4): 367-393. 
 
Effective asparaginase levels have been defined as activity of ≥ 0.1 International 
Units per mL. Clinical trials with asparaginase Erwinia chrysanthemi 
demonstrated that 100% of patients achieved effective asparaginase levels at 
48 and 72 hours (n=35 and n=13, respectively) following the third total dose 
when given on a Monday, Wednesday, Friday schedule using the IM route of 
administration. In a multicenter study characterizing the pharmacokinetic profile 
of 25,000 International Units/m2 Erwinaze® given intravenously over one hour 
on the same dosing schedule of Monday, Wednesday, Friday for 2 consecutive 
weeks, 83% (20/24) and 43% (9/21) of evaluable patients achieved an 
asparaginase activity level of ≥ 0.1 International Units/mL at 48 post-dose 5 and 
72 hours post-dose 6, respectively. No formal drug interaction studies have been 
performed with asparaginase Erwinia chrysanthemi. 
 
 
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 
 
Allergic reactions, anaphylaxis, 
urticaria 
Local injection site reactions, fever 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
 
 
Pancreatitis, glucose intolerance, 
thrombosis, hemorrhage, transient 
ischemic attack, disseminated 
intravascular coagulation, 
hyperbilirubinemia, alanine 
aminotransferase increased, 
aspartate aminotransferase 
increased, hyperglycemia, 
hyperammonemia, vomiting, 
nausea, abdominal pain, headache, 
diarrhea, seizure 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of L-asparaginase have been noted in animals. Adequate, 
well-controlled studies of asparaginase Erwinia chrysanthemi have NOT been conducted. It is not 
known whether asparaginase Erwinia chrysanthemi will cause fetal harm or affect the ability to 
reproduce. It is not known if asparaginase Erwinia chrysanthemi is excreted into breast milk. The 
use of asparaginase Erwinia chrysanthemi should be avoided in pregnant or lactating patients. 
(L) Toxicity may also occur later. 
 
 
 


 
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Formulation and Stability: 
Asparaginase Erwinia chrysanthemi is supplied as a sterile, white lyophilized 
powder for reconstitution in a clear glass vial with a 3 mL capacity. Each vial 
contains 10,000 International Units of asparaginase Erwinia chrysanthemi and 
the following inactive ingredients: glucose monohydrate (5.0 mg), sodium 
chloride (0.5 mg). Store intact vials between 2°C and 8°C (36° to 46ºF). Protect 
from light. 
 
 
Guidelines for Administration: 
See Treatment and Dose Modification sections of the protocol. 
 
Erwinia asparaginase can be administered by intramuscular injection or by 
intravenous infusion. Use appropriate precautions for preparation of a hazardous 
agent. Visually inspect the powder in vial for foreign particles or discoloration 
prior to reconstitution.  
 
For intramuscular administration, the contents of each vial should be 
reconstituted by slowly adding 1 mL or 2 mL of sterile, preservative-free NS to 
the inner vial wall. The final concentration is 10,000 International Units per mL 
when using 1 mL for reconstitution or 5,000 International Units per mL when 
using 2 mL for reconstitution. Gently mix or swirl the contents to dissolve the 
contents of the vial. Do not shake or invert the vial. The resulting solution should 
be clear and colorless. Discard if any particulate matter or protein aggregates are 
visible. Withdraw the appropriate dosing volume into a polypropylene syringe 
within 15 minutes of reconstitution. Polycarbonate luer-lok syringes from B-D 
(1 mL) are also acceptable (personal communication, EUSA Pharma). Discard 
any unused drug; do not save or use any unused drug remaining the in the vial. 
No more than 2 mL should be given at any one injection site. Doses larger than 
2 mL should be divided and given in separate administration sites. 
 
For intravenous use, slowly inject the appropriate volume of reconstituted 
solution into a Normal Saline 100 mL infusion bag; do not shake or squeeze the 
bag. Infuse Erwinia asparaginase over 1-2 hours. Do not infuse other intravenous 
drugs through the same intravenous line while infusing Erwinia asparaginase. 
Please see http://www.erwinazesupply.com to check which batches may require 
the use a 0.2-micron, low protein binding, in-line filter for IV administration. 
 
Administer the dose within a 4 hour time period from reconstitution. If the 
dose is not used within this time period, discard the dose. Do not freeze or 
refrigerate the reconstituted solution.  
 
The product used in Australia has an 8 hour expiry (from Porton Biopharma, 
Salisbury, UK).  
 
Have available during and after the infusion: antihistamine, epinephrine, oxygen, 
and IV corticosteroids. Observe patient for ONE hour after administration for 
signs of hypersensitivity reactions. 
 
 
Drug Ordering: 
In the United States, asparaginase Erwinia chrysanthemi (Erwinaze) is 
distributed by McKesson Plasma and Biologics. Verify your institution has a 


 
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contract with McKesson Plasma and Biologics before ordering. If not, contact 
McKesson at 877-625-2566 for assistance setting up an account. 
 
Orders may be placed online or via phone, fax, or email. 
Orders may be placed online via http://Connect.McKesson.com 
Orders may be submitted via fax to 888-752-7626 
Orders may be submitted via email or MPBOrders@McKesson.com 
Email all other information requests to MPB@McKesson.com 
Regular order hours: M-F 9:00 am – 7:30 pm EST; 
Emergency order after hours services (24/7/365): 877-625-2566 
Orders placed by 7:30 pm EST will ship the next day.  
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6). 
c) 
Refusal of protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of planned therapy. 
f) 
Physician determines it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (bilirubin, ALT (SGPT) or serum creatinine) 
are outside the parameters required for eligibility prior to the start of systemic 
chemotherapy (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
 
 
Patients who are removed from protocol therapy during Cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent. Patients who are removed from protocol therapy in subsequent cycles 
should have the necessary observations to ensure adequate clinical care.  
 
Patients who are off protocol therapy are to be followed until they meet the criteria for 
Off Study (see below). Ongoing adverse events, or adverse events that emerge after the 
patient is removed from protocol therapy, but within 30 days of the last dose of 
investigational agent, must be followed and reported via RAVE and SAE Report 
submitted via RAVE (if applicable).  Follow-up data will be required unless consent is 
withdrawn. 
 
 
Off Study Criteria 
 
a) 
Thirty days after the last dose of the investigational agent. 
b) 
Death 
c) 
Lost to follow-up 


 
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d) 
Withdrawal of consent for any required observations or data submission. 
e) 
Enrollment onto another COG therapeutic (anti-cancer) study  
f) 
Patient did not receive protocol treatment after study enrollment 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
 
Sample Size and Study Duration 
 
The minimum number of evaluable patients required for is 4. The projected maximum 
number of evaluable patients required for the dose confirmation is 15. This allows for 6 
patients at each of 2 dose levels and 20% inevaluability. Therefore, this part is expected 
to be completed within 8-15 months assuming that 1-2 patients per month are enrolled 
into the study. An absolute maximum of 30 patients is possible in the unlikely event that 
each of 2 dose levels is expanded to 12 patients because of DLTs of different classes and 
20% inevaluability. If this scenario occurred, the study would be expected to be 
completed within 15-30 months.  
 
Up to six evaluable patients with relapsed B- or T-ALL/LL will be enrolled at the 
RP2D/MTD for further pharmacokinetic and efficacy assessment. This part of the study 
would be expected to be accrue over 6-12 months. 
 
The entire study is expected to accrue a maximum of 21 patients and is expected to be 
completed within 14-27 months. An absolute maximum accrual of 36 patients for the 
entire protocol is expected to take up to 18-36 months. 
 
 
Definitions 
 
 Evaluable for Adverse Events 
Any patient who receives at least one dose of the study drug(s) or who 
experiences a dose-limiting toxicity is considered evaluable for Adverse 
Events. In addition, for the dose-confirmation portion during Cycle 1, patients 
must receive at least 85% of the prescribed dose per protocol guidelines and 
must have the appropriate toxicity monitoring studies performed to be 
considered evaluable for dose limiting toxicity. Patients who do not have DLT 
and are not considered evaluable for toxicity will be replaced. 
 
 Maximum Tolerated Dose 
• 
The MTD will be the maximum dose at which fewer than one-third of 
patients experience DLT (See Section 5.5) during Cycle 1 of therapy.  
 
• 
In the unlikely event that two DLTs observed out of 6 evaluable patients are 
different classes of Adverse Effects (e.g. hepatotoxicity and 
myelosuppression), AND all of the following conditions are met, expansion 
of the cohort to 12 patients will be considered:  
 
•  One of the DLTs does not appear to be dose- and/or drug-related 
•  The Adverse Effects are readily reversible 
•  The study chair, DVL statistician, DVL committee chair or vice chair, 
and IND sponsor all agree that expansion of the cohort is acceptable 
 


 
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If fewer than 1/3 of patients in the expanded cohort experience dose-limiting 
toxicities, the dose confirmation can proceed. 
 
• 
The DLTs observed in the expansion pharmacokinetic (PK)/efficacy phase 
(Part B) will be counted towards the total number of DLTs observed at the 
MTD during the dose confirmation portion of the study. If ≥ 1/3 of the cohort 
of patients at the MTD (during the dose confirmation plus the PK expansion) 
experience DLT then the MTD will be exceeded.  
 
 
Dose Confirmation and Determination of MTD 
 
The rolling six phase 1 trial design will be used for the conduct of this study. 17 Two to 
six patients can be concurrently enrolled onto a dose level, dependent upon (1) the 
number of patients enrolled at the current dose level, (2) the number of patients who have 
experienced DLT at the current dose level, and (3) the number of patients entered but 
with tolerability data pending at the current dose level.  Accrual is suspended when a 
cohort of six has enrolled or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the 
cohort, the number of DLTs observed, and the number of participants at risk for 
developing a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). 
For example, when three participants are enrolled onto a dose cohort, if toxicity data is 
available for all three when the fourth participant entered and there are no DLTs, the dose 
is escalated and the fourth participant is enrolled to the subsequent dose level. If data is 
not yet available for one or more of the first three participants and no DLT has been 
observed, or if one DLT has been observed, the new participant is entered at the same 
dose level. Lastly, if two or more DLTs have been observed, the dose level is de-
escalated. This process is repeated for participants five and six. In place of suspending 
accrual after every three participants, accrual is only suspended when a cohort of six is 
filled. When participants are inevaluable for toxicity, they are replaced with the next 
available participant if escalation or de-escalation rules have not been fulfilled at the time 
the next available participant is enrolled onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the current 
dose level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the 
study is suspended to accrual: 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
3 
0 
3 
0 
Escalate** 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
4 
0 
4 
0 
Escalate** 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 


 
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5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
5 
0 
5 
0 
Escalate** 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
the MTD has been exceeded and dose escalation will be stopped (see Section 11.2.2 for 
exception to rule). 
 
In addition to determination of the RP2D/MTD, a descriptive summary of all toxicities 
will be reported. 
 
 
Inclusion of Children, Women and Minorities 
 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual 
to past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies.  Efforts will be made to extend the accrual to a 
representative population, but in a Phase 1 trial which will accrue a limited number of 
patients, a balance must be struck between patient safety considerations and limitations 
on the number of individuals exposed to potentially toxic or ineffective treatments on the 
one hand and the need to explore gender, racial, and ethnic aspects of clinical research on 
the other. If differences in outcome that correlate to gender, racial, or ethnic identity are 
noted, accrual may be expanded or additional studies may be performed to investigate 
those differences more fully. 
 
 
Pharmacokinetic and Correlative Studies and Response Analysis 
 
A descriptive analysis of pharmacokinetic (PK) parameters of palbociclib will be 
performed to define systemic exposure, drug clearance, and other pharmacokinetic 
parameters. The PK parameters will be summarized with simple summary statistics, 
including means, medians, ranges, and standard deviations (if numbers and distribution 
permit).   
 
While the primary aim of this study is to evaluate the toxicity of palbociclib, patients will 
have disease evaluations performed as indicated in Section 8.1.  Disease response will be 
assessed according to leukemia/lymphoma specific criteria (Section 12.0) and will be 
reported descriptively. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in 
nature. 
 
 
Study Design  
 


 
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This study is designed using a rolling six model to confirm the recommended phase 2 
dose or maximally tolerated dose of Palbociclib in patients with relapsed B- or T-
ALL/LL.  Once the RP2D/MTD is established a non-statistical feasibility expansion 
cohort of up to 6 evaluable patients will be enrolled. If the proportion of patients who 
experience a DLT in cycle 1 is >33% at any time, then the study will suspend enrollment 
pending DVL leadership discussion. 
 
 
Method of Analysis  
 
Response will be determined as defined in Section 12.0. A report on the efficacy 
assessment will be posted on the completed disease stratum as part of a semi-annual 
study committee meeting book report.  
 
Toxicities for patients will be described separately for the expansion cohort.  
 
 
 
12.0 
EVALUATION CRITERIA 
 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov). 
 
 
Response Criteria for Patients with Relapsed Acute Lymphoblastic Leukemia 
 
 Bone marrow status 
M1 < 5% blasts in a bone marrow aspirate with at least 200 cells counted.  
M2 5 - 25% lymphoblasts in a bone marrow aspirate with at least 200 cells 
counted. 
M3 > 25% lymphoblasts in a bone marrow aspirate with at least 200 cells 
counted. 
 
 Leukemia Relapse 
• Isolated Bone Marrow Relapse: Patients with an M2 or M3 marrow at any 
point after achieving initial remission without involvement of any 
extramedullary site. Morphologic relapse should be confirmed using flow 
cytometry, FISH and/or cytogenetics or molecular techniques. 
• CNS Relapse: Positive cytomorphology and WBC ≥ 5/μL OR clinical signs 
of CNS leukemia such as facial nerve palsy, brain/eye involvement, or 
hypothalamic syndrome that are, in the opinion of the investigator, more 
likely due to recurrent CNS leukemia than to alternative causes (e.g., viral 
infection or chemotherapy toxicity). If any CSF evaluation shows positive 
cytomorphology and WBC < 5/µL, a second CSF evaluation is 
recommended within 2 - 4 weeks. While identification of a leukemic clone in 
CSF by flow cytometry (TdT, CD19, CD10, etc.) or FISH for diagnostic 
karyotypic abnormality may be useful, definitive evidence of CNS 


 
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involvement (i.e. WBC ≥ 5/µL OR clinical signs of CNS leukemia) is 
required for the diagnosis of a CNS relapse. 
• Testicular Relapse: Confirmation by testicular biopsy preferred but not 
required if associated with marrow relapse. 
• Combined Relapse: M2 or M3 marrow at any point after achieving 
remission with concomitant CNS and/or testicular relapse. 
 
 Complete Response (CR) 
Complete response (CR) is defined as an M1 marrow (< 5% blasts) with no 
evidence of circulating blasts or extramedullary disease and with peripheral count 
recovery, defined as absolute neutrophil count (ANC) ≥ 500/µL and platelet 
count ≥ to 50,000/µL without transfusion for 7 days. 
Resolution of extramedullary disease (non-CNS, non-testicular) is defined as 
improvement of any nodal or organ disease with lesion resolution to < 1cm or 
FDG-PET SUV improved to Deauville 3 or less (< hepatic or mediastinal uptake) 
if initially FDG-avid.  Skin lesions must be clinically resolved. 
 
 Complete Response with Incomplete Count Recovery (CRi) 
Complete response with incomplete recovery of peripheral blood counts (CRi) is 
defined as an M1 marrow (< 5% blasts) with no evidence of circulating blasts or 
extramedullary disease and with an ANC < 500/µL and/or platelet count < 
50,000/µL. 
 
 Partial Response (PR) 
Complete disappearance of circulating blasts and achievement of M2 marrow 
status if M3 originally, without new sites of extramedullary disease, and with 
recovery of absolute neutrophil count (ANC ≥ 500/µL). Complete response in the 
marrow without resolution of extramedullary sites is a PR. 
 
 Stable Disease (SD) 
Patient does not satisfy the criteria for PD, or has recovery of ANC ≥ 500/µL and 
fails to qualify for CR, CRi, or PR. 
 
 Progressive Disease (PD) 
An increase of at least 25% in the absolute number of bone marrow leukemic 
cells, development of new sites of extramedullary disease, or other laboratory or 
clinical evidence of PD, with or without recovery of ANC or platelets. 
 
 MRD Negative 
Patients will be considered MRD negative if their bone marrow has less than 
0.01% blasts by flow cytometric evaluation. MRD should be performed by a 
COG approved laboratory.  
 
 Treatment Failure: Failure to achieve the following: 
 
Marrow 
CNS 
Testicular/Other 
Extramedullary 
Disease 
End of 
Cycle 1 
M1 
CNS1 
Clinical and imaging 
resolution (if 


 
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applicable) of all sites 
of extramedullary 
disease 
 
 
Central Nervous System (CNS) involvement of leukemia or lymphoma at relapse 
 
CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, 
regardless of the number of WBCs. 
 
CNS 2: In CSF, presence < 5/μL WBCs and cytospin positive for blasts, or ≥ 5/μL WBCs 
but negative by Steinherz/Bleyer algorithm: 
CNS 2a: < 10/μL red blood cells (RBCs); < 5/μL WBCs and cytospin positive 
for blasts; 
CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts; and 
CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but 
negative by Steinherz/Bleyer algorithm (see below); 
 
CNS 3: In CSF, presence of ≥ 5/μL WBCs and cytospin positive for blasts and/or 
clinical signs of CNS leukemia or lymphoma: 
CNS 3a: < 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts; 
CNS 3b: ≥ 10/μL RBCs, ≥ 5/μL WBCs and positive by Steinherz/Bleyer 
algorithm (see below); 
CNS 3c: Clinical signs of CNS leukemia or lymphoma (such as facial nerve 
palsy, brain/eye involvement or hypothalamic syndrome). 
 
Method of evaluating initial traumatic lumbar punctures (LPs) 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is 
traumatic and contains ≥5 WBC/μL and blasts, the following Steinherz/Bleyer algorithm 
should be used to distinguish between CNS2 and CNS3 disease: 
 
CSF WBC 
> 
2X 
Blood WBC 
CSF RBC 
Blood RBC 
 
A patient with CSF WBC ≥5/μL blasts, whose CSF WBC/RBC ratio is 2X greater than 
the blood WBC/RBC ratio, has CNS disease at diagnosis. 
 
Example: 
CSF WBC = 60/μL; CSF RBC = 1,500/μL; blood WBC = 46000/μL; 
blood RBC = 3.0 X 106/μL: 
 
60  
 = 0.04 
> 
2X  46,000  
 
= 
0.015 
1,500 
3.0 X 106 
 
 
 
Response Criteria for Patients with Relapsed Lymphoblastic Lymphoma 
 
 Response Criteria 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in 
Pediatric Non-Hodgkin Lymphoma Criteria34, with modification from the 
Lugano classification. 34-36 Patients will LL must have either measurable or 
evaluable disease.  


 
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 Evaluable for objective response:  
Only those patients who have measurable disease present at baseline and have 
received at least one dose of protocol therapy will be considered evaluable for 
response. These patients will have their response classified according to the 
definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of Course 1 will also be considered evaluable.) 
 
 Disease Parameters 
 
 Measurable disease:  
A measurable node must have an LDi (longest diameter) greater 
than 1.5 cm. A measurable extranodal lesion should have an LDi 
greater than 1.0 cm. All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
 Non-measured disease:  
All other lesions (including nodal, extranodal, and assessable 
disease) should be followed as nonmeasured disease (e.g., 
cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial 
effusions, ascites).   
 
 Target lesions: 
For patients staged with CT, up to six of the largest target nodes, 
nodal masses, or other lymphomatous lesions that are 
measurable in two diameters (longest diameter [LDi] and 
shortest diameter) should be identified from different body 
regions representative of the patient’s overall disease burden and 
include mediastinal and retroperitoneal disease, if involved. 
 
 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 2 weeks prior to the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
 Clinical lesions:  
Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and 
≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). 
In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is 
recommended.  
 


 
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 Conventional CT and MRI:  
The major response designations will be established by CT or 
MRI of involved sites in conjunction with morphologic 
evaluation of bone marrow (BM) if involved at diagnosis. With 
growing concerns about the risks of cumulative ionizing 
radiation exposure to children from CT, MRI could be 
considered as an alternative to CT for evaluating non-pulmonary 
disease sites. e.g., assessment of abdominal/pelvic disease. As 
with CT, if an MRI is performed, the technical specifications of 
the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with 
CT, the modality used at follow-up should be the same as was 
used at baseline and the lesions should be measured/assessed on 
the same pulse sequence. It is beyond the scope of the response 
guidelines to prescribe specific MRI pulse sequence parameters 
for all scanners, body parts, and diseases. Ideally, the same type 
of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans. Pulse 
sequences should include at a minimum, axial and coronal fat-
saturated FRFSE-T2, coronal T1 and axial and coronal post-
gadolinium fat-saturated T1 weighted imaging. Body scans 
should be performed with breath-hold scanning techniques, if 
possible. 
 
 PET-CT:  
At present, the low dose or attenuation correction CT portion of 
a combined PET-CT is not always of optimal diagnostic CT 
quality. However, if the site can document that the CT performed 
as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for International Pediatric Non-Hodgkin 
Lymphoma Response Criteria measurements and can be used 
interchangeably with conventional CT in accurately measuring 
cancer lesions over time. Note, however, that the PET portion of 
the CT introduces additional data, which may bias an 
investigator if it is not routinely or serially performed.   
 
 Ultrasound: 
 Ultrasound is not useful in assessment of lesion size and should 
not be used as a method of measurement. Ultrasound 
examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next. If 
new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT 
in selected instances. 
 


 
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 Endoscopy, Laparoscopy:  
The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to 
confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an 
endpoint. 
 
 FDG-PET:  
For patients with a positive PET scan at diagnosis, PET can be 
used to follow response in addition to a CT scan using the 
International Pediatric Non-Hodgkin Lymphoma Response 
Criteria.34 
 
 Response Criteria 
 
 Evaluation of Measurable Disease 
 
Complete Response (CR):  Disappearance of all disease. CT or MRI should be free of residual 
mass or evidence of new disease. FDG-PET should be negative. 
 
CR unconfirmed (Cru):  
Residual mass is negative by FDG-PET; no new lesions by imaging 
examination; no new and/or progressive disease elsewhere 
 
Partial Response (PR): 
50% decrease in SPD (the sum of the products of the largest diameter 
and the perpendicular diameter for a tumor mass) on CT or MRI; FDG-
PET may be positive (Deauville score or 4 or 5 with reduced lesional 
uptake compared with baseline); no new and/or PD; morphologic 
evidence of disease may be present in BM if present at diagnosis; 
however, there should be 50% reduction in percentage of lymphoma 
cells 
 
Progressive Disease (PD): For those with > 25% increase in SPD on CT or MRI, Deauville score 
4 or 5 on FDG-PET with increase in lesional uptake from baseline, or 
development of new morphologic evidence of disease in BM 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
 Evaluation of Non-measured Lesions (CT-based response, PET/CT based 
response not applicable)36 
 
Complete Response (CR): 
Absent non-measured lesions.  
 
Partial response (PR): 
Absent/normal, regressed, lesions, but no increase. 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): New or clear progression of preexisting non-measured lesions. 
 


 
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 Evaluation of organ enlargement36 
 
Complete Response (CR): 
Regress to normal  
 
Partial response (PR): 
Spleen must have regressed by > 50% in length beyond normal 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): In the setting of splenomegaly, the splenic length must increase by 50% 
of the extent of its prior increase beyond baseline. If no prior 
splenomegaly, must increase by at least 2 cm from baseline.  
 
New or recurrent splenomegaly 
 
 Duration of Response 
 
 Duration of overall response:  
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented. 
 
 Duration of stable disease:  
Stable disease is measured from the start of the treatment until 
the criteria for progression are met.  
 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to 
time of progression or death, whichever occurs first. 
 
 Response Review 
Response will be as per institutional evaluations. 
 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  Adverse events are reported in a routine manner at scheduled 
times during a trial.  (Please follow directions for routine reporting provided in the Case Report 
Forms for this protocol).  Additionally, certain adverse events must be reported in an expedited 
manner to allow for optimal monitoring of patient safety and care.  The following sections 
provide information about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered 
serious; 3) the grade (severity); and 4) whether or not hospitalization or prolongation of 
hospitalization was associated with the event. 


 
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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. 
 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 5.0.  The 
descriptions and grading scales found in the revised CTCAE version 5.0 will be 
used for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of 
specific adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
NOTE: This includes all events that occur within 30 days of the last dose of 
protocol treatment.  Any event that occurs more than 30 days after the 
last dose of treatment and is attributed (possibly, probably, or definitely) 
to the agent(s) must also be reported according to the instructions in the 
table below. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
Step 4:  Complete the MedWatch Form FDA 3500A SAE Report found on the protocol 
homepage and load into RAVE per the CRF guidelines. CTEP AERS will NOT be used 
for reporting of Serious Adverse Events 
 
 
Table A: Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  


 
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6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via  MedWatch Form 
FDA 3500A 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 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via MedWatch within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via MedWatch Form FDA 3500A in RAVE if the event occurs 
following treatment with an agent under a COG IND. 
 
 
Reporting of Adverse Events for commercial agents – AINV18P1 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.  
 


 
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COG requires the MedWatch Form FDA 3500A report to be submitted in RAVE within 
7 calendar days of learning of the event. 
 
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. 
 
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 
 
 
MedWatch Form FDA 3500A 
Possible, Probable, Definite 
MedWatch Form FDA 3500A 
 
MedWatch Form FDA 3500A 
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 that can be attributed (possibly, probably, or definitely) to the agent and is not due to 
cancer recurrence must be reported via  MedWatch reporting. 
 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via MedWatch Form FDA 3500A if the event occurs following 
treatment with an agent under a COG IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
Additional Instructions or Exceptions to SAE Expedited Reporting Requirements for Phase 1 Trials 
Utilizing an Agent under a Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not clearly due 
to progressive disease must be reported via MedWatch Form FDA 3500A in RAVE for an agent 
under a CTEP or non-CTEP IND agent per the timelines outlined in the table above. 
 
• 
Patients who become pregnant on study risk intrauterine exposure of the fetus to agents that may 
be teratogenic. For this reason, pregnancy needs to be reported in an expedited manner via 
MedWatch Form FDA 3500A in RAVE. Pregnancy needs to be followed until the outcome of 
the pregnancy is known at intervals deemed appropriate by her physicians. If the baby is born 
with a birth defect or anomaly, then a second expedited report is required. Any pregnancy loss 
must also be reported expeditiously.  
 
• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), does 
not require expedited reporting, unless it is associated with hospitalization. 
 


 
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Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
• 
Grade 1 and 2 adverse events listed in the table below do not require expedited reporting, unless it 
is associated with hospitalization. 
Category 
Adverse Events  
EYE DISORDERS 
Dry Eye 
EYE DISORDERS 
Watering Eyes 
EYE DISORDERS 
Blurred vision 
GASTROINTESTINAL DISORDERS 
Decreased Appetite 
GASTROINTESTINAL DISORDERS 
Diarrhea 
GASTROINTESTINAL DISORDERS 
Nausea 
GASTROINTESTINAL DISORDERS 
Vomiting 
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS 
Fatigue 
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS 
Fever 
INFECTIONS AND INFESTATIONS 
Infections and Infestations- 
Other, specify.  
INFECTIONS AND INFESTATIONS 
Infections and Infestations- 
Other, specify (stomatitis) 
NERVOUS SYSTEM DISORDERS 
Nervous system disorders- 
Other, specify (asthenia) 
NERVOUS SYSTEM DISORDERS  
Dysgeusia  
NERVOUS SYSTEM DISORDERS 
Headache 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Alopecia 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Dry Skin  
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
Rash Maculo-papular 
 
 
 
When to Report an Event in an Expedited Manner  
 
• 
Some adverse events require notification within 24 hours (refer to Table A) to the 
study sponsor.  
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
• 
Expedited AE reporting for this study must only use the MedWatch Form FDA 
3500A Reporting upload mechanism within Rave for AINV18P1 
 
 
Expedited Reporting Methods  
 
  SAE Expedited Reporting 


 
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To report adverse events in an expedited fashion use the MedWatch Form FDA 
3500A report template found on the protocol homepage, and submit the 
completed form via the SAE Reporting mechanism in Rave for AINV18P1. 
 
A MedWatch Form FDA 3500A must be submitted electronically via the Med 
Watch  Form FDA 3500A CRF in RAVE  
 
Send supporting documentation by email to the AINV18P1 COG Study 
Assigned Research Coordinator.  ALWAYS include the COG patient ID on 
all emailed documents. 
 
 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG case report 
forms and do not alter the guidelines for SAE Expedited reporting. 
 
 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
 If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported. 
 
 The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects.  
 
 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than or equal to Grade 1, whichever level is higher (note that the 
resolution date may therefore be different from the date at which the grade of the 
AE decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."   
 
 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
 
Other Recipients of Adverse Event Reports 
 
 Events that do not meet the criteria for SAE reporting (Section 13.2) should be 
reported at the end the cycle using the forms provided in the CRF packet (See 
Section 14.1). 
 
 COG will forward reports and supporting documentation to the Study Chair, to 
the FDA (when COG holds the IND) and to the pharmaceutical company (for 
industry sponsored trials). 
 
 Adverse events determined to be reportable must also be reported according to 
the local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 


 
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14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically to the 
COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be entered in 
RAVE with the aid of schedules and worksheets (essentially paper copies of the eRDES 
and RAVE screens) provided in the case report form (CRF) packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
 
 
 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including a Protocol Safety 
Committee.  
 
 Protocol Safety Committee 
This study will be monitored in accordance with the Children’s Oncology 
Group policy for data and safety monitoring of Phase 1 and 2 studies. In brief, 
the role of the Protocol Safety Committee (PSC) is to protect the interests of 
patients and the scientific integrity of the study. The PSC consists is constituted 
of members who will serve as advisors to the study sponsors and to assist in 
achieving the successful completion of this clinical trial and to participate in the 
evaluation of the safety and trial results. The PSC members will be 
investigators participating in Study AINV18P1 who will work with the study 
committee and study sponsors to ensure the protection of the welfare of 
subjects participating in this clinical trial and to enhance the integrity of the 
conduct of the clinical trial. The PSC members should have experience in the 
conduct of clinical trials and have knowledge of good clinical practice (GCP) 
guidelines and a general understanding of regulatory requirements for drug 
development. The PSC members should be capable of conducting discussion, 
integrating differing points of view, and moving toward consensus on 
recommendations to be provided to the study sponsors 
 
The PSC will meet on an as needed basis, at least every 6 months, to review the 
safety data for the determination of dose-limiting toxicities (DLT), feasibility 
decisions, analyses of the interim results, evaluate risk benefit throughout the 
conduct of the study and other issues relevant to the overall study conduct 
Approximately 6 weeks before each meeting of the PSC, study chairs will be 
responsible for working with the study statistician to prepare study reports for 
review by the PSC. The PSC will provide recommendations to the COG 
Developmental Therapeutics Chair and the Group Chair for the study, or to 
continue the study unchanged. Study Progress reports for institutional review 
boards will be prepared using the public data monitoring report as posted on the 


 
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COG Web site. 
 
 Monitoring by the Study Chair and Developmental Therapeutics Leadership  
The study chair will monitor the study regularly and enter evaluations of 
patients’ eligibility, evaluability, and dose limiting toxicities into the study 
database. In addition, study data and the study chair’s evaluations will be 
reviewed by the Developmental Therapeutics Chair, Vice Chair and Statistician 
on a weekly conference call. 


 
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REFERENCES 
1. 
Dickson MA: Molecular Pathways: CDK4 Inhibitors for Cancer Therapy. Clin Cancer Res, 2014 
2. 
Raetz EA, Bhatla T: Where do we stand in the treatment of relapsed acute lymphoblastic 
leukemia? Hematology Am Soc Hematol Educ Program 2012:129-36, 2012 
3. 
Ko RH, Ji L, Barnette P, et al: Outcome of patients treated for relapsed or refractory acute 
lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. J 
Clin Oncol 28:648-54, 2010 
4. 
Sun W, Malvar J, Sposto R, et al: Re-Induction Outcome for Pediatric Patients with Relapsed or 
Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: A Retrospective Cohort Study of 
the Therapeutic Advances in Childhood Leukemia Consortium. Blood 126:3760-3760, 2015 
5. 
Sicinska E, Aifantis I, Le Cam L, et al: Requirement for cyclin D3 in lymphocyte development 
and T cell leukemias. Cancer Cell 4:451-61, 2003 
6. 
Sawai CM, Freund J, Oh P, et al: Therapeutic targeting of the cyclin D3:CDK4/6 complex in T 
cell leukemia. Cancer Cell 22:452-65, 2012 
7. 
Dhillon S: Palbociclib: first global approval. Drugs 75:543-51, 2015 
8. 
Finn RS, Crown JP, Lang I, et al: The cyclin-dependent kinase 4/6 inhibitor palbociclib in 
combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-
positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 
study. Lancet Oncol 16:25-35, 2015 
9. 
Finn RS, Martin M, Rugo HS, et al: Palbociclib and Letrozole in Advanced Breast Cancer. N 
Engl J Med 375:1925-1936, 2016 
10. 
Cristofanilli M, Turner NC, Bondarenko I, et al: Fulvestrant plus palbociclib versus fulvestrant 
plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer 
that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, 
double-blind, phase 3 randomised controlled trial. Lancet Oncol 17:425-39, 2016 
11. 
Clark AS, O'Dwyer PJ, Heitjan D, et al: A phase I trial of palbociclib and paclitaxel in metastatic 
breast cancer. Journal of Clinical Oncology 32:527-527, 2014 
12. 
Gururangan S, Becher O, Leary S, et al: EPT-19 Phase I trial of palbociclib, a CDK4/6 inhibitor 
in children with retinoblastoma protein(RB1) + recurrent central nervous system (CNS) tumors 
(PBTC 042). Neuro-Oncology 18:iii28-iii28, 2016 
13. 
Raetz EA, Borowitz MJ, Devidas M, et al: Reinduction platform for children with first marrow 
relapse of acute lymphoblastic Leukemia: A Children's Oncology Group Study[corrected]. J Clin 
Oncol 26:3971-8, 2008 
14. 
Messinger Y, Gaynon P, Raetz E, et al: Phase I study of bortezomib combined with 
chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report 
from the therapeutic advances in childhood leukemia (TACL) consortium. Pediatr Blood Cancer 
55:254-9, 2010 
15. 
Raetz EA, Cairo MS, Borowitz MJ, et al: Chemoimmunotherapy reinduction with epratuzumab in 
children with acute lymphoblastic leukemia in marrow relapse: a Children's Oncology Group 
Pilot Study. J Clin Oncol 26:3756-62, 2008 
16. 
Yang C, Boyson CA, Di Liberto M, et al: CDK4/6 Inhibitor PD 0332991 Sensitizes Acute 
Myeloid Leukemia to Cytarabine-Mediated Cytotoxicity. Cancer Res 75:1838-45, 2015 
17. 
Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the timeline of pediatric phase I trials: the 
rolling six design. J Clin Oncol 26:190-5, 2008 
18. 
Stock W, Douer D, DeAngelo DJ, et al: Prevention and management of 
asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: 
recommendations of an expert panel. Leukemia & Lymphoma 52:2237-2253, 2011 
19. 
Langer T, Martus P, Ottensmeier H, et al: CNS late-effects after ALL therapy in childhood. Part 
III: neuropsychological performance in long-term survivors of childhood ALL: impairments of 
concentration, attention, and memory. Med Pediatr Oncol 38(5):320-8, 2002 


 
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20. 
Mulhern RK, Palmer SL: Neurocognitive late effects in pediatric cancer. Curr Probl Cancer 
27(4):177-97, 2003 
21. 
Harila-Saari AH, Paakko EL, Vainionpaa LK, et al: A longitudinal magnetic resonance imaging 
study of the brain in survivors in childhood acute lymphoblastic leukemia. Cancer 83(12):2608-
17, 1998 
22. 
Winick NJ, Bowman WP, Kamen BA, et al: Unexpected acute neurologic toxicity in the 
treatment of children with acute lymphoblastic leukemia. J Natl Cancer Inst. 84(4):252-6, 1992 
23. 
Van den Berg HW, Desai ZR, Wilson R, et al: The pharmacokinetics of vincristine in man: 
reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited 
elimination. Cancer Chemother Pharmacol 8(2):215-9, 1982 
24. 
Relling MV, Pui CH, Sandlund JT, et al: Adverse effect of anticonvulsants on efficacy of 
chemotherapy for acute lymphoblastic leukaemia. Lancet 356:285-90, 2000 
25. 
Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the use of antimicrobial agents 
in neutropenic patients with cancer. Clin Infect Dis 34:730-51, 2002 
26. 
Lawson SE, Harrison G, Richards S, et al: The UK experience in treating relapsed childhood 
acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study. Br J 
Haematol 108:531-43, 2000 
27. 
Thomson B, Park JR, Felgenhauer J, et al: Toxicity and efficacy of intensive chemotherapy for 
children with acute lymphoblastic leukemia (ALL) after first bone marrow or extramedullary 
relapse. Pediatr Blood Cancer 43:571-9, 2004 
28. 
Bucaneve G, Micozzi A, Menichetti F, et al: Levofloxacin to prevent bacterial infection in 
patients with cancer and neutropenia. N Engl J Med 353:977-87, 2005 
29. 
Gafter-Gvili A, Fraser A, Paul M, et al: Meta-analysis: antibiotic prophylaxis reduces mortality in 
neutropenic patients. Ann Intern Med 142:979-95, 2005 
30. 
Dvorak CC, Fisher BT, Sung L, et al: Antifungal prophylaxis in pediatric hematology/oncology: 
new choices & new data. Pediatr Blood Cancer 59:21-6 
31. 
Oren I, Haddad N, Finkelstein R, et al: Invasive pulmonary aspergillosis in neutropenic patients 
during hospital construction: before and after chemoprophylaxis and institution of HEPA filters. 
Am J Hematol 66:257-62, 2001 
32. 
Ariffin H, Omar KZ, Ang EL, et al: Severe vincristine neurotoxicity with concomitant use of 
itraconazole. J Paediatr Child Health 39:638-9, 2003 
33. 
Bermudez M, Fuster JL, Llinares E, et al: Itraconazole-related increased vincristine neurotoxicity: 
case report and review of literature. J Pediatr Hematol Oncol 27:389-92, 2005 
34. 
Sandlund JT, Guillerman RP, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol 33:2106-11, 2015 
35. 
Sandlund JT, Guillerman RP, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. Journal of Clinical Oncology 33:2106-2111, 2015 
36. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32:3059-68, 2014 
37. 
Zhang J, Ding L, Holmfeldt L, et al: The genetic basis of early T-cell precursor acute 
lymphoblastic leukaemia. Nature 481:157-63, 2012 
38. 
Mullighan CG: Molecular genetics of B-precursor acute lymphoblastic leukemia. J Clin Invest 
122:3407-15, 2012 
39. 
Chung CT, Santos Gda C, Hwang DM, et al: FISH assay development for the detection of 
p16/CDKN2A deletion in malignant pleural mesothelioma. J Clin Pathol 63:630-4, 2010 
 
 


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


 
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APPENDIX II: ASSESSING THE BIOLOGICAL ACTIVITY OF PALBOCICLIB: 
CORRELATIVE BIOLOGY STUDY SUMMARY 
 
Bone marrow and/or peripheral blood samples will be collected at three time points: 
 
• 
Pre-study (marrow) 
• 
Day 4 (peripheral blood)- Peripheral blood samples should be collected PRIOR to administration of 
Day 4 chemotherapy, if  absolute blast count is > 1000/mm3 
• 
Day 32 + 2 days (marrow, if a patient has persistent disease) 
 
 
The pre-study and Day 32 time points coincide with times when bone marrow aspirates are performed as 
a part of routine clinical care so that extra procedures will not be done exclusively for research tests. 
Peripheral blood also can be substituted or used to augment bone marrow samples if the absolute blast 
count is >1000/μL: 10 mL per samples (<10 kg) or 15 mL (≥10 kg).   
 
To substitute peripheral blood, patients must have an initial absolute blast count of at least 1000 
lymphoblasts/μL. To calculate the absolute blast percentage, multiply the total WBC by the % peripheral 
blasts:  
 
(WBC)(% blast)(1000) = absolute blast count/μL  
 
As an example, if the patient has a WBC of 10 and 50% blasts, the absolute blast count is:  
(10)(.5)(1000) = 5000/μL 
 
Lymphoblasts will be isolated from bone marrow or blood within 4 hours of collection using Ficoll-Paque 
Plus (Amersham Biosciences, Brown Deer, WI) at participating centers to avoid potential artifacts 
associated with prolonged sample storage or shipping.  Blasts will then be frozen and batch shipped on 
dry ice to the Carroll/Aifantis labs for DNA and protein purification.  Participating sites will be required 
to purify the blast population from bone marrow by density gradient centrifugation using Ficoll-Paque 
Plus and freeze samples prior to batch shipment of the samples to our laboratory for analysis (see protocol 
for Ficoll purification below in section 2.0).  
 
 
PBMC Isolation by Ficoll  
 
Marrow blasts will be purified within 4 hours of collection at local centers using the protocol described 
below. 
Required materials: 
- 
5 – 15 mL fresh marrow or blood sample 
- 
Ficoll-Hypaque solution 
- 
PBS 
- 
50 mL falcon tubes 
- 
1.8 mL Cryotubes 
- 
DMSO 
- 
Fetal Bovine Serum (FBS) 
- 
1 mL individually wrapped sterile transfer pipettes 
 
Instructions: 
 
All steps are carried out using a sterile technique, at room temperature – unless noted otherwise. 
 


 
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1) Fresh marrow or blood samples should be stored at 4°C prior to isolation. 
2) Prepare all required materials and label falcon tubes.  
3) Fill a tube with a volume of Ficoll-Hypaque that is equal to the volume of the marrow or blood 
sample (Ficoll:Marrow or Blood ratio is 1:1). 
4) In a second tube, mix marrow or blood sample with an equal volume of PBS (1:1) 
5) Slowly overlay diluted marrow or blood sample from Step 4 onto Ficoll-Hypaque from Step 3, 
avoiding the mixing of marrow or blood with Ficoll: 
• 
Suggestion: tilt the falcon tube with Ficoll at a 45° angle and add the diluted sample to 
the side of the tube using 10 mL serological pipette. You should see a clear interface. 
6) Centrifuge 30 minutes at 400xg with BRAKE OFF. 
7) Gently aspirate and discard the top layer of plasma. The layer below is the PBMC layer (buffy 
coat). Remove it using a 1 mL individually wrapped sterile transfer pipette and transfer to a new 
50 mL tube leaving behind the clear Ficoll layer and bottom red blood layer. 
8) Bring volume to 45 mL with PBS and mix cells by gently inverting several times. 
9) Centrifuge 20 minutes at 200xg with the BRAKE ON. 
10) Without disturbing the pellet, remove and discard the supernatant. 
11) Bring volume to 10 mL with PBS and mix cells to obtain a uniform suspension.  
• 
Note: Pelleted cells will start dying if not resuspended immediately. 
12) Count the cells and determine their viability. Keep the samples on ice during the count. 
13) Centrifuge for 10 minutes at 400xg with the BRAKE ON. 
14) Without disturbing the pellet, remove and discard the supernatant. 
15) Resuspend cell pellet at 10 million cells per mL in 95% FBS/5% DMSO. Aliquot 10 million cells 
(1 mL) per cryo-tube and slow freeze at -80°C.   
 
Cryopreserved marrow samples will be shipped on dry ice:  
 
Ship the sample by Federal Express Priority Overnight delivery to:  
 
Carroll/Aifantis Labs 
        
 
 
Laura and Isaac Perlmutter Cancer Center at NYU Langone 
 
 
 
522 First Avenue, Smilow Building 12 Floor, Room 1211 
 
 
 
Tel: 212.263.2327 • Fax: 212.263.9190  
New York, NY 10016   
 
FedEx account # 320569834 
 
 
• 
Email or call Nikki Evensen, PhD (Nikki.Evensen@nyulangone.org; 212-263-2327 or 516-765-
6832) when the sample is being shipped. 
• 
Do not ship samples for delivery on a weekend or holiday. 
 
 
 


 
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APPENDIX III:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
This is not an inclusive list. Because the lists of these agents are constantly changing, it is important to 
regularly consult frequently updated medical references. 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong Inducers 
Moderate 
Inducers 
acalabrutinib5 
alfentanil4,5  
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
idelalisib 
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 
isavuconazole 
mifepristone 
nilotinib 
verapamil 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
dabrafenib 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifapentin 
 
 
 


 
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ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4  
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) 
may inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 7.5 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors)  


 
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APPENDIX IV: ADDITIONAL INFORMATION FOR CORRELATIVE BIOLOGY STUDIES: 
DETERMINING THE BIOLOGICAL ACTIVITY OF PALBOCICLIB  
 
Overview:  Assays will be performed prior to and following palbociclib administration as summarized in 
Table 1 to determine the efficiency of cell cycle inhibition. 
 
 
Table 1.  Correlative Biology Studies  
 
 
Pre-study 
Day 4 
Day 32* 
Targeted DNA 
sequencing to identify 
somatic mutations in 
both T-ALL and B-
ALL samples 
 
 
X 
 
 
CDKN2A deletions 
(using FISH) 
X 
 
 
RB1 expression and 
RB1 phosphorylation 
status 
(Immunoblotting) 
X 
X** 
X 
p27Kip1 expression 
(Immunoblotting) 
X 
X** 
X 
Cyclin D3 and CDK4/6 
protein expression 
(Immunoblotting) 
X 
X** 
X 
Cell cycle analysis 
(response to 
Palbociclib) 
X 
X** 
X 
Peripheral blood 
absolute blast count 
X 
X** 
 
* End of therapy analyses in patients with persistent disease. End of therapy analyses must be obtained on Day 
32 + 2 days.  
** Submit peripheral blood samples if absolute blast count is >1000/mm3 
 
Experimental Design: 
Bone marrow and peripheral blood samples (5 mL) will be collected at the time points summarized in 
Table 1.  The pre-study and Day 32 time points coincide with times when bone marrow aspirates are 
performed as a part of routine clinical care so that extra procedures will not be done exclusively for 
research tests. Peripheral blood also can be substituted or used to augment bone marrow samples if the 
absolute blast count is >1000/mm3: 10 mL per samples (<10 kg) or 15 mL (≥10 kg).   
 
Lymphoblasts will be isolated from bone marrow within 4 hours of collection using Ficoll-Paque Plus 
(Amersham Biosciences, Brown Deer, WI) at participating COG Phase 1 centers to avoid potential 
artifacts associated with prolonged sample storage or shipping.  Blasts will then be frozen and batch 
shipped on dry ice to the Carroll/Aifantis labs for DNA and protein purification.  One third of the cells 
will be used for DNA sequencing and two thirds of cells per sample will be used for protein expression.  
Freshly harvested blasts will be collected and fixed prior to shipment for the proposed cell cycle analyses 
(see Appendix II for details regarding samples processing). 
 


 
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1) Western Blotting (immunoblotting). Expression of RB1, phospho-RB1, Cyclin D3, CDK4, 
CDK6 and p27Kip1 will be performed using Western Blotting (immunoblotting).T-ALL and B-
ALL blast cells will be resuspended in lysis buffer (20mM Tris, pH8; 150mM NaCl; 0.1% SDS; 
0.5% Na-Deoxycholate) containing protease inhibitors (Roche, Basel, Switzerland) and sonicated 
for 30 sec at 4 watts, incubated on ice for 10 minutes and centrifuged at 14,000rpm for 10 min at 
4ºC. The resulting supernatant will be collected and protein concentration will be determined 
using the DC Protein assay (Bio-Rad). 25 µg of protein will be fractionated by 15% SDS-PAGE 
and transferred to Immobilon-P membrane (Millipore, Billerica, MA). Immunoblotting will be 
performed with the following primary antibodies and dilutions: anti-RB1 (BD Pharmingen, cat 
#554162), anti-Cyclin D3 (Santa Cruz Biotechnology, sc-6283), anti-p27KIP1/CDKN1B (Santa 
Cruz Biotechnology, sc-393305), anti-CDK4 (Santa Cruz Biotechnology, sc-23896) and anti-
CDK6 (Santa Cruz Biotechnology, sc-7961) and anti-actin, 1:4000 (Abcam, #8227), as a loading 
control. HRP-conjugated anti-rabbit IgG, 1:10,000 and anti- mouse IgG, 1:10,000 (NA934V, 
NA931V, GE Healthcare,) will be used as the secondary antibody. Reactive proteins will be 
visualized using ECL Plus (Amersham Life Sciences). 
 
2) Targeted DNA sequencing to identify somatic mutations. ALL samples will be sequenced 
using a custom mutational gene panel that includes the most frequently mutated genes in B-ALL 
and T-ALL.37,38 These include RB1, PAX5, IKZF1, CRLF2, CREBBP, NOTCH1, FBXW7, NRAS, 
KRAS, IL7Ra, JAK1, JAK2, JAK3, TET2, RUNX1, EP300, IKZF1-3, EZH2, EED, SUZ12, 
GATA3, RUNX1 and PHF6. Samples will pre- prepped as previously described, DNA libraries 
will be generated and sequenced using the Ion Torrent platform that enables us to sequence 
reliably small numbers of cells. This technology is available at NYU Langone Medical Center.  
 
3) Dual-Colour FISH for detection of CDKN2A deletions. CDKN2A deletions will be detected 
using fluorescence in situ hybridization (FISH) analysis as it is currently done in solid tumors. 
Dual-color FISH will be performed using a commercially available Spectrum Orange-labelled 
locus specific p16 (9p21) probe and Spectrum Green-labelled chromosome 9 centromeric probe 
[Vysis LSI p16 (9p21) SpectrumOrange/CEP9 SpectrumGreen Probe; Abbott Laboratories, Des 
Plaines, Illinois, USA] as previously described.39 ALL cells will be cytospun on slides for FISH 
analysis. After washing in 2X standard saline citrate for 5 min, sections will be digested with 
pepsin (37 500 U in 0.1 N HCl) (Sigma, St Louis, Missouri, USA) at 37°C for 10–25 min. Slides 
will be co-denatured with the probes, allowed to hybridize and washed according to the 
manufacturer's protocol. Slides will be analyzed, blinded from the clinical data, using a Zeiss 
microscope (Axioplan 2, Jena, Germany) equipped with the appropriate filters. A minimum of 
100 non-overlapped intact (uniform DAPI staining with intact nuclear contours) interphase nuclei 
of consecutive cells in at least two different areas of the section will be scored.  
 
4) Cell Cycle Analysis. We will use standard flow cytometry protocols to combine surface staining 
for T-ALL markers (CD1a, CD3, CD4, CD8) and intracellular staining for the cell cycle (and 
apoptosis) markers Ki67 and DAPI. For intracellular Ki67 and DAPI staining in T-ALL cells, 
following staining of surface antigens, bone marrow/peripheral T-ALL cells will be fixed with 
4% paraformaldehyde and permeabilized with 0.1% saponin prior to addition of anti-Ki67 (BD 
Biosciences) and 2 µg/mL DAPI.  A similar procedure will be followed for B-ALL. 
 
As an early measure of response to single agent palbociclib, the absolute peripheral blast count will be 
measured at baseline and after 72 hours of drug exposure.   
 
For pre- and post-treatment measurements of absolute peripheral blast count protein expression, pairwise 
comparisons will be made using Fisher’s exact test and paired t-test or an equivalent nonparametric tests 
as appropriate.  Baseline expression of cell cycle proteins and the presence of somatic mutations and 
CDKN2A deletions will be correlated with treatment response. These analyses will be descriptive and 
exploratory in nature. 
 


 
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AINV18P1 
 
 
 
 
 
Version Date:   01/23/20                                                              
Page 92 
 
 
APPENDIX V-A: Palbociclib Capsule Dosing Nomogram  
 
Drug doses should be adjusted based on the BSA calculated from height and weight measured within 7 
days prior to the beginning of each cycle.   
 
Palbociclib is available as 75 mg and 100 mg capsules. Patients receiving doses > 75 mg/day may 
take either the capsule or liquid formulation. Patients receiving < 75 mg/day of palbociclib must 
receive the liquid formulation (See Appendix V-B for dosing preparation of palbociclib liquid 
formulation.) 
 
Palbociclib Dose Assignment: 50 mg/m2 
(Dose Level 1) 
BSA (m2) 
Total Daily Dose 
(mg/day) 
Dose Reduction for Toxicity 
(mg/day) 
< 1.37 
Use liquid formulation 
(see Appendix V-B) 
Reduce dose by 30%. Use liquid 
formulation (see Appendix V-B) 
 
  1.37-1.74 
75 
Reduce dose by 30%. Use liquid 
formulation (see Appendix V-B) 
≥ 1.75 
100 
75 
 
 
Palbociclib Dose Assignment: 35 mg/m2 
(Dose Level -1) 
BSA (m2) 
Total Daily Dose (mg/day) 
Dose Reduction for Toxicity 
(mg/day) 
 
  <1.95 
Use liquid formulation       
(see Appendix V-B) 
off protocol therapy 
> 1.95 
75 
off protocol therapy 
 
 
 
 
 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
AINV18P1 
 
 
 
 
 
Version Date:   01/23/20                                                              
Page 93 
 
 
APPENDIX V-B: PALBOCICLIB DOSING PREPARATION (LIQUID FORMULATION) 
 
Drug doses should be adjusted based on the BSA calculated from height and weight measured within 7 
days prior to the beginning of the cycle.   
 
Patients receiving doses > 75 mg/day may take either the capsule or liquid formulation. (See 
Appendix V-A for dosing nomogram for palbociclib capsule formulation).  
 
Patients receiving < 75 mg/day of palbociclib must receive the liquid formulation.  
 
Patients receiving the liquid formulation who experience dose-limiting toxicity should have their 
dose reduced by 30%, so that patients receive 70% of the original prescribed dose. 
 
The concentration of palbociclib liquid formulation is 25 mg/mL.  
 
Calculated doses < 18.75 mg should be prepared in oral syringes ≤ 1 mL with dosing volumes of 
palbociclib liquid formulation rounded to the nearest 0.1 mL (2.5 mg). Calculated doses > 18.75 mg 
should be prepared in 5 mL oral syringes with dosing volumes of palbociclib liquid formulation rounded 
to the nearest 0.2 mL (5 mg). It is recommended that oral dosing syringes should be only filled up to 75% 
of the maximum volume.  
 
To calculate dosing volumes for each patient based on BSA, the following formula should be used: 
 
Dosing Volume (mL) = Prescribed Dose (mg/m2) x BSA (m2) 
       
 
 
 
 
 
 
 25 (mg/mL) 
 
Round dosing volumes according to the above rules. 
Examples: 
• 
Patient BSA 0.33 m2, Dose Level 1 (50 mg/m2)  Calculated Dose = 16.5 mg PO daily 
         
Calculated Volume (mL) = (50 mg/m2 x 0.33 m2) / (25 mg/mL) = 0.66 mL  
Final Dosing Volume (mL) =  0.7 mL (rounded to nearest 0.1 mL for doses ≤ 18.75 mg) 
Final Dose to be administered = 0.7 mL x 25 mg/mL = 17.5 mg 
 
• 
Patient BSA 1.66 m2, Dose Level -1 (35 mg/m2)  Calculated Dose = 58.1 mg PO daily 
 
             Calculated Volume (mL) = (35 mg/m2 x 1.66 m2) / (25 mg/mL) =2.324 mL  
Final Dosing Volume (mL) = 2.4 mL (rounded to the nearest 0.2 mL for dose > 18.75 
mg) 
Final Dose to be administered = 2.4 mL x 25 mg/mL = 60 mg 


  
                                     THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
                        
AINV18P1 
 
                                                                                                                                                                                                  
Version Date:   01/23/20                                                              
Page 94 
 
Cycle 1  
APPENDIX VI: 
THERAPY DELIVERY MAP (TDM) (PATIENTS WITH ALL) 
 
Therapy Delivery Map – Cycle 1 
This Therapy Delivery Map (TDM) relates to Cycle 1. Cycle 1 lasts 32 days. This TDM can be used for all dose levels of 
palbociclib. Please record the dose level below. This TDM is intended to serve as a tool to assist in scheduling the required 
observations for the study; the schedule indicated in the chart below should be considered an example. The actual schedule must 
comply with the timing of required observations per Section 8 of the protocol. This form is to be completed and uploaded into 
RAVE at the end of Cycle 1. 
____________________________ 
Accession # 
____________________________ 
Patient COG ID number 
_______________________ 
Institution 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Palbociclib  
IND #141416  
PO (or NG-
Tube) 
Dose Level -1: 35 mg/m2 
Dose Level 1: 
50 mg/m2 
Once daily on Days 1-21 
Dose Level -1: MAX dose 75 mg 
Dose Level 1: MAX dose 100 mg 
Intrathecal Cytarabine (IT 
ARAC):  All patients on Day 1 
(before CNS status is known) 
IT 
Age (yrs) 
Dose 
1-1.99 
30 mg 
2-2.99 
50 mg 
   ≥3 
70 mg 
1@ 
Note age-based dosing  
 
@Patients with known CNS3 disease at the time of 
study enrollment may receive triple intrathecal 
chemotherapy on Day 1 as a substitute for intrathecal 
cytarabine, at the discretion of the treating investigator. 
Patients are NOT to receive both intrathecal triples and 
intrathecal cytarabine on Day 1, regardless of CNS 
status. 
Intrathecal Methotrexate (IT 
MTX):  CNS1 and 2 
 
 
IT 
Age (yrs) 
Dose 
1-1.99 
8 mg 
 2-2.99 
10 mg 
 3-8.99 
12 mg 
    ≥9 
15 mg 
18,32 
Note age-based dosing  
 
Intrathecal Triple Therapy (ITT): 
Methotrexate (MTX)/ 
Hydrocortisone (HC)/Cytarabine 
(ARAC) if CNS3 
 
 
IT 
Age (yrs) 
Dose 
   1-1.99 
MTX:8mg, 
                   HC: 8mg, 
                         ARAC: 16mg 
    2-2.99 
MTX: 10mg 
                   HC: 10 mg 
                       ARAC: 20 mg 
    3-8.99 
MTX: 12 mg 
                  HC: 12 mg 
                       ARAC: 24 mg 
        ≥9 
MTX: 15 mg 
                  HC: 15 mg 
                       ARAC: 30 mg 
1@, 4, 11, 18, 25 
Note age-based dosing  
 
@Patients with known CNS3 disease at the time of 
study enrollment may receive triple intrathecal 
chemotherapy on Day 1 as a substitute for intrathecal 
cytarabine, at the discretion of the treating investigator. 
Patients are NOT to receive both intrathecal triples and 
intrathecal cytarabine on Day 1, regardless of CNS 
status.  
DOXOrubicin (DOXO) 
slow IV push or 
infusion over 1-
15 min 
60 mg/m²/dose 
4 
Administer through the tubing of a rapidly infusing 
D5W or 0.9% NaCL solution 
 
PredniSO(LO)NE (PRED)* 
 
PO 
40 mg/m²/day divided BID or 
TID 
4-31 
 
VinCRIStine (VCR) 
IV push over 1 
min+  
1.5 mg/m²/dose (MAX dose 2 
mg) 
4, 11, 18, 25 
+ + Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg  


  
                                     THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
                        
AINV18P1 
 
                                                                                                                                                                                                  
Version Date:   01/23/20                                                              
Page 95 
 
Cycle 1  
Pegaspargase (PEG-ASP) 
IV  
over 1-2 hours 
2500 International units/m²/dose 
5, 18 
Administer IV infusion through the tubing of a rapidly  
infusing D5W or 0.9% NaCL solution. 
See section 5.1 for special precautions with 
pegaspargase administration. 
* IV methylprednisolone may be given at 80 % of the oral predniSONE or predniSOLONE dose.  
 
                                                                                                                 
NOTE: All patients should receive trimethoprim/sulfamethoxazole (TMP/SMX) at a dose of TMP 2.5 mg/kg/dose (maximum dose 160 mg/dose) by mouth twice daily on 2 or 3 sequential days 
per week.
 
Assigned Dose Level ______ 
Ht _________cm 
Wt _________kg 
 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Palbociclib 
________ mg 
IT ARAC  
______ mg 
IT MTX 
(CNS 1 and 2)  
______ mg 
Intrathecal Triple 
Therapy (CNS3): 
   MTX/  HC/  ARAC 
__mg/___ mg/___mg 
DOXO  
______ mg 
 PRED 
____ mg BID or TID  
VCR 
______ mg 
PEG-ASP  
______ IU 
Studies to be 
obtained 
 
 
1 
________ mg 
______ mg 
 
______ mg 
 
 
 
 
 
 
 
2 
________ mg 
 
 
 
 
 
 
 
i 
 
 
3 
________ mg 
 
 
 
 
 
 
 
 
 
 
4 
________ mg 
 
 
   MTX/  HC/  ARAC 
__mg/___ mg/___mg  
______ mg 
__ mg  __ mg    __ mg 
                   
______ mg 
 
a, b, f,  h, j, p, q,n 
 
 
5 
________ mg 
 
 
 
 
 
_______ IU 
 
 
 
6 
________ mg 
 
 
 
 
 
 
 
 
 
7 
________ mg 
 
 
 
 
 
 
 
 
 
8 
________ mg 
 
 
 
 
 
 
f 
 
 
9 
________ mg 
 
 
 
 
 
 
 
 
 
10 
________ mg 
 
 
 
 
 
 
 
 
 
11 
________ mg 
 
 
   MTX/  HC/  ARAC 
__mg/___ mg/___mg  
 
______ mg 
 
a, b, f, h, i, j,n 
 
 
12 
________ mg 
 
 
 
 
 
 
i 
 
 
13 
________ mg 
 
 
 
 
 
 
 
 
 
14 
________ mg 
 
 
 
 
 
 
 
 
 
15 
________ mg 
 
 
 
 
 
 
f 
 
 
16 
________ mg 
 
 
 
 
 
 
 
 
 
17 
________ mg 
 
 
 
 
 
 
 
 
 
18 
________ mg 
 
______ mg 
   MTX/  HC/  ARAC 
__mg/___ mg/___mg  
 
______ mg 
______ IU 
a, b, f, h, j,n 
 
 
19 
________ mg 
 
 
 
 
 
 
 
 
 
20 
________ mg 
 
 
 
 
 
 
 
 
 
21 
________ mg 
 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
f 
 
 
23 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
 
25 
 
 
 
   MTX/  HC/  ARAC 
__mg/___ mg/___mg  
 
______ mg 
 
a, b, f, h, j,n 
 
 
26 
 
 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 


  
                                     THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
                        
AINV18P1 
 
                                                                                                                                                                                                  
Version Date:   01/23/20                                                              
Page 96 
 
Cycle 1  
 
 
29 
 
 
 
 
 
 
 
f 
 
 
30 
 
 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
 
 
32^ 
 
 
______ mg 
 
 
 
 
 
a, b, c, d, f, h, j, l, 
m, o, n 
^ Abnormal laboratory tests must be re-checked by Day 42 since some toxicities require resolutions to ≤ Grade 2 or baseline by Day 42 (see DLT criteria). 
See Section 6.0 for Dose Modifications for Adverse Events and Section 7.0 and the COG Member website for Supportive Care Guidelines 


  
                                 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
                   AINV18P1 
 
                                                                                                                                                                                                  
Version Date:   01/23/20                                                              
Page 97 
 
Cycle 1  
 
Required Observations in Cycle 1  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated below. For 
information related to prestudy observations please refer to Section 8.0  
 
a. 
History 
b. Physical exam with vital signs 
c. 
Height, weight, BSA 
d. Performance status 
e. 
Pregnancy test: Women of childbearing potential require a negative pregnancy test 
prior to starting treatment; sexually active patients must use an acceptable method of 
birth control. Abstinence is an acceptable methods of birth control. All women of 
childbearing potential must have a pregnancy test done every cycle prior to initiation 
of a new cycle. 
f. 
CBC, differential, platelets: Twice weekly during Cycle 1. If patients have Grade 4 
neutropenia or thrombocytopenia, CBCs should be checked at least every other day 
until recovery to Grade 3 or until the criteria for dose limiting toxicity are met. 
g. Urinalysis  
h. Electrolytes including Ca++ 
i. 
Pharmacokinetics (required): See Section 8.2 for details. 
j. 
Creatinine, ALT, bilirubin 
k. Albumin 
l. 
ECHO or gated radionuclide study  
m. 12-lead EKG  
n. Patient Diary 
o. Bone Marrow Aspirate for morphology and MRD. Must be performed on Day 32 + 
2 days.  
p. Absolute Blast Count; Absolute blast count should be performed on Day 4 prior to 
administration of chemotherapy. 
q. Correlative Biology Studies See Section 8.3 for details. 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 


  
                                 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
                   AINV18P1 
 
                                                                                                                                                                                                  
Version Date:   01/23/20                                                              
Page 98 
 
Cycle 1  
APPENDIX VII: 
THERAPY DELIVERY MAP (TDM) (PATIENTS WITH LL) 
 
Therapy Delivery Map – Cycle 1 
This Therapy Delivery Map (TDM) relates to Cycle 1. Cycle 1 lasts 32 days. This TDM can be used for all dose levels of 
palbociclib. Please record the dose level below. This TDM is intended to serve as a tool to assist in scheduling the required 
observations for the study; the schedule indicated in the chart below should be considered an example. The actual schedule must 
comply with the timing of required observations per Section 8 of the protocol. This form is to be completed and uploaded into 
RAVE at the end of Cycle 1. 
____________________________ 
Accession # 
____________________________ 
Patient COG ID number 
_______________________ 
Institution 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Palbociclib  
IND #141416  
PO (or NG-
tube) 
Dose Level -1: 35 mg/m2 
Dose Level 1: 
50 mg/m2 
Once daily on Days 1-21 
Dose Level -1: MAX dose 75 mg 
Dose Level 1: MAX dose 100 mg 
Intrathecal Cytarabine (IT 
ARAC):  All patients on Day 1 
(before CNS status is known) 
IT 
Age (yrs) 
Dose 
1-1.99 
30 mg 
2-2.99 
50 mg 
   ≥3 
70 mg 
1@ 
Note age-based dosing  
 
@Patients with known CNS3 disease at the time of 
study enrollment may receive triple intrathecal 
chemotherapy on Day 1 as a substitute for intrathecal 
cytarabine, at the discretion of the treating investigator. 
Patients are NOT to receive both intrathecal triples and 
intrathecal cytarabine on Day 1, regardless of CNS 
status. 
Intrathecal Methotrexate (IT 
MTX):  CNS1 and 2 
 
 
IT 
Age (yrs) 
Dose 
1-1.99 
8 mg 
 2-2.99 
10 mg 
 3-8.99 
12 mg 
    ≥9 
15 mg 
18,32 
Note age-based dosing  
 
Intrathecal Triple Therapy (ITT): 
Methotrexate (MTX)/ 
Hydrocortisone (HC)/Cytarabine 
(ARAC) if CNS3 
 
 
IT 
Age (yrs) 
Dose 
   1-1.99 
MTX:8mg, 
                   HC: 8mg, 
                         ARAC: 16mg 
    2-2.99 
MTX: 10mg 
                   HC: 10 mg 
                       ARAC: 20 mg 
    3-8.99 
MTX: 12 mg 
                  HC: 12 mg 
                       ARAC: 24 mg 
        ≥9 
MTX: 15 mg 
                  HC: 15 mg 
                       ARAC: 30 mg 
1@, 4, 11, 18, 25 
Note age-based dosing  
 
 
@Patients with known CNS3 disease at the time of 
study enrollment may receive triple intrathecal 
chemotherapy on Day 1 as a substitute for intrathecal 
cytarabine, at the discretion of the treating investigator. 
Patients are NOT to receive both intrathecal triples and 
intrathecal cytarabine on Day 1, regardless of CNS 
status. 
DOXOrubicin (DOXO) 
slow IV push or 
infusion over 1-
15 min 
60 mg/m²/dose 
4 
Administer through the tubing of a rapidly infusing 
D5W or 0.9% NaCL solution 
 
PredniSO(LO)NE (PRED)* 
 
PO 
40 mg/m²/day divided BID or 
TID 
4-31 
 
VinCRIStine (VCR) 
IV push over 1 
min+  
1.5 mg/m²/dose (MAX dose 2 
mg) 
4, 11, 18, 25 
+ + Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg  


  
                                 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
                   AINV18P1 
 
                                                                                                                                                                                                  
Version Date:   01/23/20                                                              
Page 99 
 
Cycle 1  
Pegaspargase (PEG-ASP) 
IV  
over 1-2 hours 
2500 International units/m²/dose 
5, 18 
Administer IV infusion through the tubing of a rapidly 
infusing D5W or 0.9% NaCL solution. 
See section 5.1 for special precautions with 
pegaspargase administration. 
 
    * IV methylprednisolone may be given at 80 % of the oral predniSONE or predniSOLONE dose.                                                                                                                                                                                                
NOTE: All patients should receive trimethoprim/sulfamethoxazole (TMP/SMX) at a dose of TMP 2.5 mg/kg/dose (maximum dose 160 mg/dose) by mouth twice daily on 2 or 3 sequential days 
week.Assigned Dose Level ______ 
Ht _________cm 
Wt _________kg 
 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
Palbociclib 
________ mg 
IT ARAC  
______ mg 
IT MTX 
(CNS 1 and 2)  
______ mg 
Intrathecal Triple 
Therapy (CNS3): 
   MTX/  HC/  ARAC 
__mg/___ mg/___mg 
DOXO  
______ mg 
 PRED 
____ mg BID or TID  
VCR 
______ mg 
PEG-ASP  
______ IU 
Studies to be 
obtained 
 
 
1 
________ mg 
______ mg 
 
 
 
 
 
 
 
 
 
2 
________ mg 
 
 
 
 
 
 
 
i 
 
 
3 
________ mg 
 
 
 
 
 
 
 
 
 
 
4 
________ mg 
 
 
   MTX/  HC/  ARAC 
__mg/___ mg/___mg  
______ mg 
__ mg  __ mg    __ mg 
                   
______ mg 
 
a, b, f,  h, j,n 
 
 
5 
________ mg 
 
 
 
 
 
_______ IU 
 
 
 
6 
________ mg 
 
 
 
 
 
 
 
 
 
7 
________ mg 
 
 
 
 
 
 
 
 
 
8 
________ mg 
 
 
 
 
 
 
f 
 
 
9 
________ mg 
 
 
 
 
 
 
 
 
 
10 
________ mg 
 
 
 
 
 
 
 
 
 
11 
________ mg 
 
 
   MTX/  HC/  ARAC 
__mg/___ mg/___mg  
 
______ mg 
 
a, b, f, h, i, j,n 
 
 
12 
________ mg 
 
 
 
 
 
 
i 
 
 
13 
________ mg 
 
 
 
 
 
 
 
 
 
14 
________ mg 
 
 
 
 
 
 
 
 
 
15 
________ mg 
 
 
 
 
 
 
f 
 
 
16 
________ mg 
 
 
 
 
 
 
 
 
 
17 
________ mg 
 
 
 
 
 
 
 
 
 
18 
________ mg 
 
______ mg 
   MTX/  HC/  ARAC 
__mg/___ mg/___mg  
 
______ mg 
______ IU 
a, b, f, h, j,n 
 
 
19 
________ mg 
 
 
 
 
 
 
 
 
 
20 
________ mg 
 
 
 
 
 
 
 
 
 
21 
________ mg 
 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
f 
 
 
23 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
 
25 
 
 
 
   MTX/  HC/  ARAC 
__mg/___ mg/___mg  
 
______ mg 
 
a, b, f, h, j,n 
 
 
26 
 
 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
 
f 


  
                                 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
                   AINV18P1 
 
                                                                                                                                                                                                  
Version Date:   01/23/20                                                              
Page 100 
 
Cycle 1  
 
 
30 
 
 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
 
 
32^ 
 
 
______ mg 
 
 
 
 
 
a, b, c, d, f, h, j, l, 
m, o, p, q, r, s,n 
^ Abnormal laboratory tests must be re-checked by Day 42 since some toxicities require resolutions to ≤ Grade 2 or baseline by Day 42 (see DLT criteria). 
See Section 6.0 for Dose Modifications for Adverse Events and Section 7.0 and the COG Member website for Supportive Care Guidelines.


  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
 
   AINV18P1 
                                                                                                                                                                                                      Page 3 of 3                                     
Version Date:   01/23/20                                                              
Page 101 
 
Cycle 1  
 
Required Observations in Cycle 1  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated below. For information related to 
prestudy observations please refer to Section 8.0. 
 
a. 
History 
b. Physical exam with vital signs 
c. 
Height, weight, BSA 
d. Performance status 
e. 
Pregnancy test: Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually active patients must use an 
acceptable method of birth control. Abstinence is an acceptable methods of birth control.  
f. 
CBC, differential, platelets: Twice weekly during Cycle 1. If patients have Grade 4 neutropenia or thrombocytopenia, CBCs should be checked at least 
every other day until recovery to Grade 3. 
g. Urinalysis  
h. Electrolytes including Ca++ 
i. 
Pharmacokinetics (required): See Section 8.2 for details. 
j. 
Creatinine, ALT, bilirubin 
k. Albumin 
l. 
ECHO or gated radionuclide study  
m. 12-lead EKG  
n. Patient Diary 
o. Chest and neck CT. Obtain chest CT for all LL patients at baseline and on Day 32. The baseline chest CT may be delayed until the patient is stable. A 
PET-CT can be used instead of a CT. 
p. Abdomen/Pelvis CT or MRI. If scans are negative at baseline, not further imaging is needed on Day 32. A PET-CT can be used instead of a CT. 
q. PET scan (recommended) 
r. 
Bone scan. Bone scan only if patient has symptoms; perform at Day 32 only if patient has disease at baseline. May substitute a PET scan for a bone scan, 
however, a bone scan is preferred for bone symptoms.  
s. 
Bilateral bone marrow aspirates and biopsies for morphology. LL should have bone marrow aspirates and biopsies on Day 32 + 2 days  if ≥ 5% marrow 
involvement was present at diagnosis  
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD CLINICAL CARE.  
Comments 
(Include any held doses, or dose modifications) 
 
 
 


  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AINV18P1 
 
                                                                                                                      
Version Date:   01/23/20                                                              
Page 102 
 
APPENDIX VIII:  PHARMACOKINETIC STUDY FORM  
 
COG Pt ID # _______________ 
 
 
 
Cycle 1, Day 1 Date: _____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg  
 
Body Surface Area: ______m2  
 
Palbociclib Dose Level: ______mg/m2    Palbociclib Total Daily Dose: ______mg 
 
Palbociclib Route of Administration (oral solution/tablet): _____________ 
 
Blood samples (2-3 mL) will be collected in K2 EDTA (lavender-top) tubes 
• 
Day 1 of Cycle 1: pre-dose, and at 1, 2, 4, 8 and 24 hours post-dose of palbociclib.  
• 
Day 11 of Cycle 1: pre-dose, and at 1, 2 and 4, 8 and 24 hours post-dose of palbociclib. 
 
 
 
 
 
 
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time  
Actual Date 
Sample 
Collected 
Actual Time 
Sample Collected 
(24-hr clock) 
1 
Day 1 
Prior to palbociclib dose on Day 1 
___/___/___ 
|__|__| : |__|__| 
Palbociclib Dose on Day 1 ____mg       Date:___/___/___       Time: |__|__| : |__|__| 
2 
Day 1 
1 hr after palbociclib dose 
___/___/___ 
|__|__| : |__|__| 
3 
Day 1 
2 hr after palbociclib dose 
___/___/___ 
|__|__| : |__|__| 
4 
Day 1 
4 hr after palbociclib dose 
___/___/___ 
|__|__| : |__|__| 
5 
Day 1 
8 hr after palbociclib dose 
___/___/___ 
|__|__| : |__|__| 
6 
Day 2 
24 (±2) hrs after Day 1 palbociclib dose 
(prior to day 2 dose) 
___/___/___ 
|__|__| : |__|__| 
Palbociclib Dose on Day 2 ____mg       Date:___/___/___       Time: |__|__| : |__|__| 
Vincristine Dose on Day 11 _____mg      Date:___/___/___       Time: |__|__| : |__|__| 
7 
Day 11 
Prior to palbociclib dose on Day 11 
___/___/___ 
|__|__| : |__|__| 
Palbociclib Dose on Day 11  ____mg      Date:___/___/___       Time: |__|__| : |__|__| 
8 
Day 11 
1 hr after palbociclib dose 
___/___/___ 
|__|__| : |__|__| 
9 
Day 11 
2 hr after palbociclib dose 
___/___/___ 
|__|__| : |__|__| 
10 
Day 11 
4 hr after palbociclib dose 
___/___/___ 
|__|__| : |__|__| 
11 
Day 11 
8 hr after palbociclib dose 
___/___/___ 
|__|__| : |__|__| 
12 
Day 12 
24 (±2) hrs after Day 11 palbociclib dose 
(prior to day 12 dose)  
___/___/___ 
|__|__| : |__|__| 
Palbociclib Dose on Day 12 ____mg       Date:___/___/___       Time: |__|__| : |__|__| 
 
One copy of this Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should be sent with 
the samples to the address listed in Section 8.2.6.  See Section 8.2 for detailed guidelines for packaging and shipping 
PK samples.   
 
Signature: _________________________________________                    Date:___________________ 
 
(site personnel responsible for collection of samples) 
 
 


  
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AINV18P1 
 
                                                                                                                      
Version Date:   01/23/20                                                              
Page 103 
 
APPENDIX IX:  CORRRELATIVE BONE MARROW AND PERIPHERAL BLOOD STUDIES 
FORM (ONLY FOR PATIENTS WITH ALL) 
 
COG Pt ID # _______________ 
ACC # _______________          Cycle 1, Day 1 Date: __________  
Please do not write patient names on this form or on samples. 
 
Institution: _____________________________________________________ 
 
Body Surface Area: ____ m2 
Dose Level: ________mg/m2 
Total Dose: _______mg/day 
 
• 
Bone marrow samples (5 mL) will be obtained prior to starting Cycle 1 and on Day 32 + 2 days, if persistent 
disease (≥5% blasts).  
• 
Peripheral blood will be collected on Day 4 (15 mL if weight > 10 kg, 10 mL if weight ≤ 10kg) if absolute 
blast count is >1000/mm3. 
• 
Peripheral blood also can be substituted or used to augment bone marrow samples if the absolute blast count 
is >1000/μL: 10 mL per samples (<10 kg) or 15 mL (≥10 kg).   
 
Collection of Bone Marrow or Peripheral Blood 
Bone marrow or peripheral blood should be collected in a heparinized (green top) tube. 
 
Sample 
No. 
Time Point 
Cycle 1 
Sample Type/Scheduled 
Collection Time 
Actual 
Palbociclib 
Dose Given 
Actual Date 
Sample 
Collected or 
Dose Given 
Actual Time 
Collected or  
Dose Given 
(24-hr clock) 
1 
Pre-study 
 Bone marrow (preferred) or 
peripheral blood if absolute 
blast count > 1000/mm3 
Pre-Day 1 dose 
 
___/____/___ 
|__|__| : |__|__| 
Day 1 Dose 
________mg  
___/____/___ 
|__|__| : |__|__| 
Day 4 Absolute Blast Count 
________mm3 
2 
Day 4  
(PRIOR to 
chemotherapy 
administration) 
 Peripheral blood if absolute 
blast count > 1000/mm3 
 
___/____/___ 
|__|__| : |__|__| 
                                                                       Day 4 Dose 
________mg 
___/____/___ 
|__|__| : |__|__| 
3 
Day 32 
 Bone marrow if persistent 
disease (≥5% blasts) 
 
___/____/___ 
|__|__| : |__|__| 
 
Sample Processing (See Appendix X for details) 
Lymphoblasts will be isolated from bone marrow or blood within 4 hours of collection using Ficoll-Paque Plus 
(Amersham Biosciences, Brown Deer, WI) at participating COG centers to avoid potential artifacts associated with 
prolonged sample storage or shipping.  Blasts will then be frozen and batch shipped on dry ice to the 
Carroll/Aifantis labs for DNA and protein purification. Samples can be shipped to arrive Monday-Friday.  Ship 
samples to: 
Carroll/Iannis Aifantis Labs 
        
 
 
Laura and Isaac Perlmutter Cancer Center at NYU Langone 
 
 
 
522 First Avenue, Smilow Building 12 Floor, Room 1211 
 
 
 
Tel: 212.263.2327 • Fax: 212.263.9190  
       
 
 
New York, NY 10016    FedEx account # 320569834 
 
Email or call Nikki Evensen (Nikki.Evensen@nyumc.org; 212-263-2327) when the sample is being 
shipped. 
 
Do not ship samples for delivery on a weekend or holiday. 
 
 


  
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If this form will be used as a source document, the site personnel responsible for collection the samples must 
sign and date this form below: 
 
Signature: ___________________________________________             Date:______________________ 


  
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APPENDIX X: CORRELATIVES STUDIES GUIDE 
 
 
 
 
 
Correlative Study 
 
 
Appendix 
Sample Volume 
 
 
Tube Type 
Volume per 
sample 
Total  
 
Pharmacokinetic Study (PK) Appx. VIII 
2-3 ml 
24-36 ml 
K2 EDTA (lavender-top) 
Bone Marrow And 
Peripheral Blood Studies 
(ALL Only) 
Appx II and 
IX 
Bone marrow 
samples  
(5 mL) 
 
Peripheral 
Blood Day 4 
(15 mL if 
weight > 10 
kg, 10 mL if 
weight ≤ 10 
kg) 
Bone marrow 
samples (10 
mL) 
 
Peripheral 
Blood Day 4 
(15 mL if 
weight > 10 
kg, 10 mL if 
weight ≤ 10 
kg) 
heparinized (green top) 
tube 
Total Volume 
44-61 mL 
 
 
 
 


  
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APPENDIX XI: TOXICITY-SPECIFIC GRADING 
 
Total Bilirubin 
 
Grade 1: 
> ULN- ≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN - 3.0 x ULN 
Grade 3: 
> 3.0 x ULN -10.0 x ULN 
Grade 4: 
> 10.0 x ULN 
 
Direct Bilirubin Increase* 
 
Grade 1: 
< 3.0 mg/dl 
Grade 2: 
3.1 mg/dl - 5.0 mg/dl 
Grade 3: 
5.1 mg/dl-6.0 mg/dl 
Grade 4: 
≥ 6.1 mg/dl 
*To be reported under the SOC of ‘Investigations –Other, specify’ as ‘Direct Bilirubin Increased’ 
 
ALT: For the purpose of this study, the ULN for SGPT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
> 45 U/L - ≤ 135 U/L 
Grade 2: 
136 U/L - 225 U/L 
Grade 3: 
226 U/L - 900 U/L 
Grade 4: 
> 900 U/L 
 
AST: For the purpose of this study, the ULN for SGOT is 50 U/L regardless of baseline. 
 
Grade 1: 
> 50 U/L - ≤ 150 U/L 
Grade 2: 
151 U/L -250 U/L 
Grade 3: 
251 U/L -1000 U/L 
Grade 4: 
> 1000 U/L 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 x ULN - 5.0 x ULN 
Grade 3: 
> 5.0 x ULN -20.0 x ULN 
Grade 4: 
> 20.0 x ULN 
 
 
 


  
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APPENDIX XII: PATIENT DIARY FOR PALBOCICLIB  
 
Specific Instructions for use of capsule or liquid formulation: 
Complete each day with the time and dose given for palbociclib. Palbociclib will be given by mouth once daily on 
days 1-21. Palbociclib capsules should be taken with food. Palbociclib oral solution can be taken with or without 
food. Take at approximately the same time each day. If a dose is accidentally skipped leave that day blank. Make 
note of other drugs and supplements taken under the Comments section below. Palbociclib capsules should not be 
opened or crushed but should be swallowed whole. Store capsules or oral solution bottles upright at room 
temperature. If a patient vomits after taking palbociclib, the dose should not be repeated. Avoid grapefruit or 
grapefruit juice for the duration of the protocol therapy. It a dose is inadvertently missed, do not make it up. If a dose 
is missed and the next dose is more than 12 hours away, the missed dose should be administered.  If the next dose is 
less than 12 hours away, the missed dose should not be administered. Missed doses should not be made up. Inform 
your study doctor or nurse if a dose is missed. Add the dates to the calendar below and return the completed diary 
and the empty liquid formulation bottle(s) or any leftover liquid formulation to your institution after each treatment 
cycle.  
 
 
EXAMPLE: 
Capsule 
Formulation 
 
For each day please indicate if palbociclib was 
taken as a capsule OR as liquid formulation. 
Comments 
(Describe any missed or 
extra doses, if NG tube 
was used, vomiting 
and/or bothersome 
effects.) 
WEEK 1 
Date 
Time 
 # of palbociclib 
capsules taken 
OR 
Amount of palbociclib 
liquid formulation 
taken (mL) 
75 mg 
100 mg 
Day 1 
1/15/19 
8:30 
AM 
X 
 
 
 
She felt nauseated an hour 
after taking the drug but 
did not vomit. 
Day 2 
1/16/19 
11:00 
AM 
X 
 
 
 
 
  
EXAMPLE: 
liquid 
formulation 
 
For each day please indicate if palbociclib was 
taken as a capsule OR as liquid formulation. 
Comments 
(Describe any missed or 
extra doses, if NG tube 
was used, vomiting 
and/or bothersome 
effects.) 
WEEK 1 
Date 
Time 
 # of palbociclib 
capsules taken 
OR 
Amount of palbociclib 
liquid formulation 
taken (mL) 
75 mg 
100 mg 
Day 1 
1/15/19 
8:30 
AM 
 
 
 
2 mL 
He took the medicine 
through and NG tube and 
felt nauseated an hour 
after taking the drug but 
did not vomit. 
Day 2 
1/16/19 
11:00 
AM 
 
 
 
2 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
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   COG Patient ID:___________   
Acc#__________      
Institution :__________________________  
Please do not write patient names on this form. 
 
 
          Cycle #: _____         Start Date: |__/__|__/__|__/__|   End Date: |__/__|__/__|__/__|  
 
           Dose Level:            mg/m2/dose                               
 
WEEK 
1 
Date 
Time 
For each day please indicate if palbociclib 
was taken as a capsule OR as liquid 
formulation. 
Comments 
(Describe any missed 
or extra doses, if NG 
tube was used, 
vomiting and/or 
bothersome effects.)  
# of palbociclib capsules 
taken 
OR 
 
Amount of 
palbociclib  
liquid 
formulation 
taken (mL) 
75 mg 
100 mg 
Day 1 
 
 
AM/PM 
 
 
 
 
 
Day 2 
 
 
AM/PM 
 
 
 
 
 
Day 3 
 
 
AM/PM 
 
 
 
 
 
Day 4 
 
 
AM/PM 
 
 
 
 
 
Day 5 
 
 
AM/PM 
 
 
 
 
 
Day 6 
 
 
AM/PM 
 
 
 
 
 
Day 7 
 
 
AM/PM 
 
 
 
 
 
 
 
COG Patient ID:___________   ACC # : _____     Institution :__________________  
Please do not write patient names on this form. 
 
 
          Cycle #: _____         Start Date: |__/__|__/__|__/__|   End Date: |__/__|__/__|__/__|  
 
           Dose Level:            mg/m2/dose                               
 
WEEK 2 
Date 
Time 
For each day please indicate if palbociclib 
was taken as a capsule OR as liquid 
formulation. 
Comments 
(Describe any missed or 
extra doses, if NG tube 
was used, vomiting and/or 
bothersome effects.)  
# of palbociclib capsules 
taken 
 
 
Amount of 
palbociclib  
liquid 
formulation 
taken (mL) 
75 mg 
100 mg 
Day 8 
 
 
AM/PM 
 
 
 
 
 
Day 9 
 
 
AM/PM 
 
 
 
 
 
Day 10 
 
 
AM/PM 
 
 
 
 
 
Day 11 
 
 
AM/PM 
 
 
 
 
 
Day 12 
 
 
AM/PM 
 
 
 
 
 
Day 13 
 
 
AM/PM 
 
 
 
 
 


  
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Day 14 
 
 
AM/PM 
 
 
 
 
 
 
 
 
 
COG Patient ID:___________   ACC # : _____     Institution :__________________  
Please do not write patient names on this form. 
 
 
          Cycle #: _____         Start Date: |__/__|__/__|__/__|   End Date: |__/__|__/__|__/__|  
 
           Dose Level:            mg/m2/dose                               
 
WEEK 3 
Date 
Time 
For each day please indicate if palbociclib 
was taken as a capsule OR as liquid 
formulation. 
Comments 
(Describe any missed or 
extra doses, if NG tube was 
used, vomiting and/or 
bothersome effects.)  
# of palbociclib capsules 
taken 
OR 
 
Amount of 
palbociclib  
liquid 
formulation 
taken (mL) 
75 mg 
100 mg 
Day 15 
 
 
AM/PM  
 
 
 
 
Day 16 
 
 
AM/PM 
 
 
 
 
 
Day 17 
 
 
AM/PM 
 
 
 
 
 
Day 18 
 
 
AM/PM 
 
 
 
 
 
Day 19 
 
 
AM/PM 
 
 
 
 
 
Day 20 
 
 
AM/PM 
 
 
 
 
 
Day 21 
 
 
AM/PM 
 
 
 
 
 
 
   
If this form will be used as a source document, the site personnel who administered the drug must sign and 
date this form below: 
 
Signature: __________________________                   Date: __________________________ 
 
(site personnel who collected samples) 
 


  
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APPENDIX XIII: POSSIBLE DRUG INTERACTIONS 
 
Doxorubicin 
 
Some drugs, food, and supplements may interact with doxorubicin.  Examples include: 
Drugs that may interact with doxorubicin* 
• 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
o Clozapine, fluoxetine, fluvoxamine, nefazodone, paroxetine  
• 
Antibiotics and Antifungals  
o Fluconazole, isavuconazole, itraconazole, ketoconazole, posaconazole, 
voriconazole 
• 
Arthritis medications  
o Leflunomide, tofacitinib 
• 
Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, Stribild®, telaprevir, tipranavir, 
zidovudine 
• 
Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• 
Heart medications  
o Amiodarone, diltiazem, dronedenarone, ranolazine, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
o Ado-trastuzumab emtansine, bevacizumab, idelalisib, trastuzumab, taxane 
derivatives 
• 
Many other drugs, including the following: 
o Aprepitant, cyclosporine, fosaprepitant, fosnetupitant, deferasirox, ivacaftor, 
mifepristone, natalizumab, netupitant  
 
Food and supplements that may interact with doxorubicin** 
• Echinacea 
• Glucosamine  
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
• Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
*Sometimes these drugs are used with doxorubicin on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.   
 
The list above does not include everything that may interact with your chemotherapy. Talk to your 
doctor before starting any new medications, over-the-counter medicines, or herbal supplements and 
before making a significant change in your diet. 
 
 
 


  
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Prednisone / Prednisolone 
 
Some drugs, food, and supplements may interact with prednisone or prednisolone.  Examples 
include: 
Drugs that may interact with prednisone or prednisolone* 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Antidiabetic medications 
• Antiretrovirals and antivirals  
o Ritonavir, telaprevir 
• Anti-seizure medications  
o Phenobarbital, phenytoin, primidone 
• Growth hormones 
• Heart medications  
o Diltiazem, 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, aspirin, cyclosporine, deferasirox, desirudin, ibuprofen, 
itraconazole, mifepristone, natalizumab, pimecrolimus, rifampin, warfarin 
 
Food and supplements that may interact with prednisone or prednisolone** 
• Echinacea 
*Sometimes these drugs are used with prednisone on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
The list above does not include everything that may interact with your chemotherapy. Talk to your 
doctor before starting any new medications, over-the-counter medicines, or herbal supplements and 
before making a significant change in your diet. 
 
Vincristine 
 
Some drugs, food, and supplements may interact with vincristine.  Examples include: 
Drugs that may interact with vincristine* 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• Antifungals  
o Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, 
voriconazole 
• Arthritis medications  
o Leflunomide, tocilizumab, tofacitinib 
• Anti-rejection medications 
o Cyclosporine 
• Antiretrovirals and antivirals  


  
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o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lapatinib, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, 
telaprevir, tenofovir, tipranavir 
• Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, carvedilol, diltiazem, dronedarone, propafenone, quinidine, 
ranolazine,  verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Aprepitant, bosentan, cobicistat, conivapatan, deferasirox, fosnetupitant, ivacaftor, 
mifepristone, modafinil, natalizumab, nefazodone, netupitant 
 
Food and supplements that may interact with vincristine** 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Sometimes these drugs are used with vincristine on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
The list above does not include everything that may interact with your chemotherapy. Talk to your 
doctor before starting any new medications, over-the-counter medicines, or herbal supplements and 
before making a significant change in your diet. 
 
Pegaspargase 
 
Some drugs, food, and supplements may interact with pegaspargase.  Examples include: 
Drugs that may interact with pegaspargase* 
o Leflunomide, natalizumab, pegloticase, tofacitinib 
 
Food and supplements that may interact with pegaspargase** 
• Echinacea 
*Sometimes these drugs are used with pegaspargase on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
The list above does not include everything that may interact with your chemotherapy. Talk to your 
doctor before starting any new medications, over-the-counter medicines, or herbal supplements and 
before making a significant change in your diet 
 
 

ICF_001.pdf: 
 
 
 
AINV18P1 
 
Version Date: 01/23/20 
 
 1 
 
This model informed consent form has been reviewed and is the official consent document 
for this study. Institutions must use the sections of this document that are in bold type in 
their entirety. Editorial changes to these sections may be made as long as they do not 
change information or intent. If the local IRB insists on making deletions or more 
substantive modifications to any of the sections in bold type, they must be justified in 
writing by the investigator at the time of the institutional audit. 
 
 
SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM 
 
AINV18P1 
 A Phase 1 Study of Palbociclib (
), a CDK 4/6 Inhibitor, in Combination with 
Chemotherapy in Children with Relapsed Acute Lymphoblastic Leukemia (ALL) or 
Lymphoblastic Lymphoma (LL) 
 
 
If you are a parent or legal guardian of a child who may take part in this study, permission from 
you is required. The assent (agreement) of your child may also be required. When we say “you” 
in this consent form, we mean you or your child; “we” means the doctors and other staff. 
 
Overview 
 
You are being asked to take part in this research study because you have been diagnosed with 
acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL). The ALL or LL has come 
back after treatment (relapsed), or is not responding to treatment (it is refractory). 
 
Taking part in this study is voluntary. You may choose not to be in this study. If you decide not to 
be in this study, you will not be penalized and you will not lose any benefits to which you are 
entitled. You will still receive medical care.  
 
The overall goal of this study is to see if this treatment plan will improve the outcome of children 
with relapsed ALL or LL by increasing the percentage of patients who achieve remission after one 
month of therapy without causing intolerable side effects. 
 
The treatment involves cancer fighting medicines called chemotherapy plus palbociclib. The 
treatment on this study takes about 32 days.  
 
The dose for the first children enrolled on the study will be based on the side effects seen in 
adults. Between 2 and 6 children will receive palbociclib at each dose.  If the side effects are too 
severe, the next group of children will receive a lower dose. Dosing is done this way because we 
do not yet know the best dose to use in children. Whatever dose you start at, your dose will not 
be increased. 
 
All people who receive cancer treatment are at risk of having side effects. In addition to killing 
tumor cells, cancer chemotherapy can damage normal tissue and produce side effects. 
 
Common side effects of chemotherapy include nausea, vomiting, hair loss, and fatigue 
(tiredness). Drugs may be given to try to prevent or decrease nausea and vomiting. Hair loss is 
usually temporary but very rarely it may be permanent. Some chemotherapy may make people 
permanently unable to have children. On rare occasions, people can get a second cancer from 
chemotherapy. This usually happens years after the chemotherapy is finished.  
 
This treatment study uses the investigational drug palbociclib. 


 
 
 
AINV18P1 
Version Date: 01/23/20 
 
 2 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The full list of risks for drug palbociclib are available in the section What side effects or risks can 
I expect from being in the study? 
 
You can ask your study doctor questions about side effects at any time.  
 
We hope that this study will help you personally, but we do not know if it will. The potential benefits 
to you associated with participation in this study are described in the section Are there benefits to 
taking part in the study? 
 
You have a choice between another treatment for ALL or LL disease and this clinical trial.  
 
The rest of this form provides detailed information about the study and what to expect should 
you decide to participate. 
 
Why am I being invited to take part in this study? 
 
You are being asked to take part in this research study because you have been diagnosed with 
ALL or LL that has come back after treatment (relapsed), or is not responding to treatment (it is 
refractory). 
 
ALL and LL are types of cancer that occur in white blood cells. ALL or LL are considered high risk 
because they can progress or return quickly. The term, risk, refers to the chance of the cancer 
coming back after treatment.  
 
This study is called a clinical trial. A clinical trial is a research study involving treatment of a 
disease in human patients. 
 
This study is being carried out by the Children’s Oncology Group (COG) Pediatric Early Phase 
Clinical Trial Network (PEP-CTN). COG is an international research group that consists of more 
than 200 hospitals that treat children with cancer in the United States, Canada, Australia, and 
Switzerland. The PEP-CTN is the group within COG that consists of 21 hospitals based in the 
United States and Canada, and participation in this study will be limited to these hospitals as well 


 
 
 
AINV18P1 
Version Date: 01/23/20 
 
 3 
as Loma Linda University Medical Center, Lucile Packard Children's Hospital Stanford University, 
Johns Hopkins University/Sidney Kimmel Cancer Center, UNC Lineberger Comprehensive 
Cancer Center, Laura and Isaac Perlmutter Cancer Center at NYU Langone, University of 
Oklahoma Health Sciences Center, Cook Children's Medical Center, and Primary Children's 
Hospital. 
 
It is common to enroll children and adolescents with cancer in a clinical trial that seeks to improve 
cancer treatment over time. Clinical trials include only people who choose to take part. You have 
a choice between another treatment for ALL or LL disease and this clinical trial. 
 
Please take your time to make your decision. You may want to discuss it with your friends and 
family. We encourage parents to include their child in the discussion and decision to the extent 
that the child is able to understand and take part. 
 
What is the current standard of treatment for this disease? 
 
We are asking if you want to participate in this study because there is not a standard treatment 
for your cancer at this point. 
 
Why is this study being done? 
 
This study will test how well palbociclib given with chemotherapy works in children and young 
adults with relapsed or refractory ALL or LL. This study is testing palbociclib in combination with 
the following chemotherapy drugs: vincristine, prednisone or prednisolone, pegaspargase and 
doxorubicin. This combination of chemotherapy drugs is called reinduction chemotherapy since 
the purpose is to get rid of as many of the cancer cells as possible after ALL or LL has come back. 
Palbociclib is experimental because it has not been proven to work in a situation like yours. 
 
Palbociclib works by stopping your cancer cells from growing. We are using palbociclib because 
it has shown promising activity against leukemia in test tubes and animals and it has been highly 
effective and approved by the US Food and Drug Administration (FDA) for the treatment of other 
cancers in adults. We do not know if palbociclib will work in ALL or LL. While palbociclib has been 
used to treat a lot of adults, it has been used in only a small number of children and there is a lot 
that we do not know about it yet.  
 
The overall goals of this study are to:  
o This treatment plan is being tested to see if it will improve the outcome of 
children with relapsed ALL or LL by increasing the percentage of patients who 
achieve remission after one month of therapy without causing intolerable side 
effects.  
 
o To find a safe dose of palbociclib that can be given with chemotherapy without 
causing severe side effects; 
o To learn what kind of side effects palbociclib can cause; 
o To learn more about how palbociclib works on leukemia and lymphoma cells;   
o To determine whether palbociclib combined with intensive reinduction 
chemotherapy is a beneficial treatment for your leukemia or lymphoma. 
 


 
 
 
AINV18P1 
Version Date: 01/23/20 
 
 4 
What will happen on this study that is research? 
 
The treatment involves a cancer fighting medicine called palbociclib plus chemotherapy. The 
treatment on this study takes about 32 days. At the end of study treatment your doctor will discuss 
further treatment options with you. Further treatment may include some type of additional 
chemotherapy followed by a bone marrow (stem cell) transplant, if possible. 
 
Palbociclib is an experimental medication that will be given by mouth once daily on Days 1-21. 
Therapy will also consist of a combination of other standard anticancer medicines, described 
below. 
 
Procedures common to all patients with relapsed/refractory ALL or LL are described in 
Attachment 1. Treatment that is standard for ALL or LL are described in Attachment 1. 
 
Some parts of the treatment on this study are different from standard therapy. These parts are 
experimental and are described below.  
 
Dose Confirmation  
The palbociclib dose for the first children enrolled on the study will be based on the side effects 
seen in adults. Between 2 and 6 children will receive palbociclib at each dose.  If the side effects 
are too severe, the next group of children will receive a lower dose. Dosing is done this way 
because we do not yet know the best dose to use in children. Whatever dose you start at, your 
dose will not be increased.    
 
You will be given specific instructions regarding how to take these medicines on this study. 
Palbociclib is given by mouth once daily on Days 1-21. Palbociclib should be taken with food. If 
you vomit after taking the medication, the dose will not be repeated. 
 
You will also be given a medication diary to fill out if you are at home each time these oral 
medicines are taken. Most people receiving this treatment, however, will be treated in the hospital. 
Use the diary to record the date and time you take the drug, and any side effects you experience. 
Also record in the diary other medications and/or supplements you are taking and whether you 
vomited or missed a dose. This diary should be returned to the clinic, along with the medication 
bottle (even if it is empty) weekly during Cycle 1 and then at the end of the cycle. This will help us 
know how much of the drug you take and how it made you feel.  
 
Diagram of Treatment that is Research 
This chart shows the treatment on this study.  
 


 
 
 
AINV18P1 
Version Date: 01/23/20 
 
 5 
 
 
Palbociclib will be given by mouth once daily on Days 1-21. Therapy will also consist of 
combinations of other anticancer medicines which are described below.  
 
The standard anticancer medicines in this trial are: doxorubicin, vincristine, pegaspargase, 
prednisone or prednisolone, cytarabine (ara-C) hydrocortisone and methotrexate. All of these 
drugs have been used extensively in the treatment of ALL or LL. Prednisone or prednisolone will 
be given by tablet or liquid taken by mouth (orally). Pegaspargase, vincristine and doxorubicin will 
be given into the bloodstream through a needle inserted into a vein or through a central line. In 
addition, cytarabine, hydrocortisone and methotrexate will be used to treat the brain and spinal 
cord. The drugs used to treat the brain and spinal cord will be given through a needle inserted 
into the spinal fluid surrounding the spinal column (this is called a “spinal tap”). 
 
Vincristine will be given IV weekly for 4 weeks, doxorubicin will be given once on Day 4 and 
pegaspargase will be given IV on Days 5 and 18.  Prednisone or prednisolone will be given by 
mouth for 28 days. A spinal tap will be done on Days 1 (cytarabine OR cytarabine, hydrocortisone, 
and methotrexate), 18 (methotrexate) and 32 (methotrexate). Your doctor will let you know if you 
will only receive cytarabine on Day 1 or if you will receive cytarabine, hydrocortisone, and 
methotrexate (the combination of these 3 drugs is called “intrathecal triple therapy”). Only patients 
with a high amount of leukemia in their spinal fluid will receive intrathecal triple therapy instead of 
intrathecal cytarabine on Day 1. Additional spinal taps with intrathecal triple therapy will be done 
weekly if leukemia is detected in the spinal fluid at diagnosis.  
 
During the study you will have tests and procedures to check for side effects and see how your 
ALL or LL is doing. These tests are part of regular cancer care, but you may have them more 
often because you are on the study:  
 
• 
Physical exam 
• 
Blood tests 
• 
Spinal taps 
• 
A repeat bone marrow at the end of therapy 
• 
Repeat studies to evaluate your cancer (CT, MRI, PET/CT, etc.) at the end of therapy 
 
 
When bone marrow testing is being done as part of your standard testing on Day 32, 5mL or 1 
teaspoon will be collected for minimal residual disease (MRD) testing. This type of testing is used 
to see whether there are any leukemia cells present after therapy.  These bone marrow samples 
are required from all patients with leukemia and are considered a standard way to measure the 
response to treatment. 
 
Copies of the scans used to diagnose your cancer and some of the tissue already taken may be 
sent to a central review center as part of COG quality control. COG does this to double check 
the hospitals’ results. 
 
Details of treatment are summarized below: 
 
Prior to starting study 
• 
Get routine blood tests, bone marrow tests, spinal tap, imaging 
Day 1 
• 
Start palbociclib once daily for Days 1-21  


 
 
 
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• 
Receive Intrathecal cytarabine (IT ARAC) OR Intrathecal Triple 
Therapy (ITT) on Day .Your doctor will let you know which drugs you’ll 
receive.  
Day 4 
• 
Continue palbociclib once daily for Days 1-21 
• 
Receive Intrathecal Triple Therapy (ITT) if CNS leukemia present 
• 
Receive doxorubicin 
• 
Begin receiving prednisone or prednisolone on Days 4-31 
• 
Receive vincristine 
Day 5 
• 
Continue palbociclib once daily for Days 1-21 
• 
Continue prednisone or prednisolone on Days 4-31 
• 
Receive pegaspargase  
Day 11 
• 
Continue palbociclib once daily for Days 1-21 
• 
Continue prednisone or prednisolone on Days 4-31 
• 
Receive Intrathecal Triple Therapy (ITT) if CNS is present at the start 
of treatment 
• 
Receive vincristine 
Day 18 
• 
Continue palbociclib once daily for Days 1-21 
• 
Continue prednisone or prednisolone on Days 4-31 
• 
Receive Methotrexate (IT MTX) if CNS leukemia is not present at the 
start of treatment 
• 
Receive Intrathecal Triple Therapy (ITT) if CNS leukemia present  
• 
Receive vincristine 
• 
Receive pegaspargase  
Day 25 
• 
Continue prednisone or prednisolone on Days 4-31 
• 
Receive Intrathecal Triple Therapy (ITT) if CNS leukemia present  
• 
Receive vincristine 
Day 31 
• 
Complete prednisone or prednisolone on Days 4-31 
Day 32 
• 
Receive Methotrexate (IT MTX) if CNS leukemia is not present at the 
start of treatment 
• 
Assess response to treatment 
 
Research Study Tests and Procedures 
 
 
 
Correlative Study 
Required/Optional? 
Sample Volume 
Volume per sample 
                    
Total 
 
Pharmacokinetic Study (PK) 
Required 
3-4 ml 
36-48 ml 
Bone Marrow And Peripheral 
Blood Studies (ALL Only) 
Optional 
Bone marrow 
samples  
(5 mL) 
 
Peripheral Blood Day 
4 (15 mL if weight > 
10 kg, 10 mL if weight 
≤ 10 kg) 
Bone marrow samples 
(10 mL) 
 
Peripheral Blood Day 
4 (15 mL if weight > 10 
kg, 10 mL if weight ≤ 
10 kg) 


 
 
 
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Total Volume 
44-61 mL 
 
Required Research Study Tests 
 
We would like to determine how much palbociclib is in your blood (pharmacokinetics). Each 
sample is about 3-4 mL (a little less than 1 teaspoon) of blood. Blood samples for 
pharmacokinetics will be taken on the following schedule: Days 1 and 11: before palbociclib is 
given and at 1, 2 and 4, 8 and 24 hours post-dose of palbociclib. Twelve samples will be taken 
over the course of the study. These samples are required from all patients on study. The 
pharmacokinetic test will be done because you are part of this study. If you were not in the study 
you would probably not have this test. 
 
 
Correlative Study 
Volume per sample 
Pharmacokinetic Study (PK) 
3-4 ml 
Total Volume 
36-48 ml 
 
 
Optional Research Study Tests (ALL Patients Only) 
We would also like to do some tests called biologic studies. These tests are important to help us 
learn more about effects of palbociclib on leukemia cells and may help children and young adults 
who receive this drug in the future. The information learned would not change the way you are 
treated, and the results of these tests will not be given to you.  
 
You do not have to do these tests if you do not want to. You can still be in the study if you do not 
want to do these tests. At the end of this consent form, there is a place to record your decision 
about taking part in each test. 
 
 
Biology Studies using Bone Marrow Samples (ALL Patients only) 
When bone marrow testing is being done as part of your standard testing before you begin therapy 
and on Day 32, we would like to request an extra sample (10 mL or about 2 teaspoons) from 
patients greater than or equal to 10 kg (26.5 pounds) or, 5 mL (about 1 teaspoon) from patients 
less than 10 kg (26.5 pounds), to evaluate the effect of palbociclib on your leukemia cells. The 
tests may help us to better learn how this drug may work.  
 
Biology Studies using Blood Samples (ALL Patients only) 
During the study, an additional blood sample will be collected on Day 4, after 3 days of palbociclib, 
to evaluate the effect of palbociclib on leukemia cells in your blood. This blood sample will be 
collected at the same time standard blood tests are performed to monitor for any side effects from 
treatment and the status of your disease. The blood samples are 15 mL (about 3 teaspoons) for 
patients greater than or equal to 10 kg (22 pounds), and 10 mL (about 2 teaspoons) from patients 
less than 10 kg (22 pounds).  The tests may help us to better learn how this drug may work.  
 
What side effects or risks can I expect from being in the study? 
 


 
 
 
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Treatment Risks 
All people who receive cancer treatment are at risk of having side effects. In addition to 
killing tumor cells, cancer chemotherapy can damage normal tissue and produce side 
effects.  
 
The table below show the most common and the most serious side effects that researchers know 
about palbociclib. There might be other side effects that researchers do not yet know about. If 
important new side effects are found, the study doctor will discuss these with you. 
 
  
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Some drugs or supplements may interact with your treatment plan. Talk to your doctor, 
pharmacist, or study team before starting any new prescription or over-the-counter drugs, 
herbals, or supplements and before making a significant change in your diet.  Supplements may 
come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. 
All forms should be avoided. 
 
The risks of standard anticancer medicines given on this study are listed in Attachment 2.  
 
Common side effects of chemotherapy include nausea, vomiting, hair loss, and fatigue 
(tiredness). Drugs may be given to try to prevent or decrease nausea and vomiting. Hair 
loss is usually temporary but very rarely it may be permanent. Some chemotherapy may 


 
 
 
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make people permanently unable to have children. On rare occasions, people can get a 
second cancer from chemotherapy. This usually happens years after the chemotherapy is 
finished.  
 
Side effects can be increased when chemotherapy drugs are combined. 
 
The most common serious side effect from cancer treatment is lowering of the number of 
blood cells resulting in anemia, increased chance of infection, and bleeding tendency. Low 
blood counts are described in the COG Family Handbook for Children with Cancer. Parents will 
be taught more about caring for their child when his or her blood counts are low.  
 
Reproductive risks 
Women should not become pregnant while on this study and for at least 3 weeks after the 
last dose of palbociclib, because the drug(s) in this study can be bad for an unborn baby. 
Men should avoid fathering a child or donating sperm while on this study and for at least 
3 months after the last dose of palbociclib, because palbociclib can be bad for an unborn 
baby. If you or your partner can get pregnant, it is important for you to use birth control or 
not have sex while on this study. Check with your study doctor about what kind of birth 
control methods to use and how long to use them. Some birth control methods might not 
be approved for use in this study. If you are a woman and become pregnant or suspect 
you are pregnant while participating in this study, please inform your treating physician 
immediately. Women should not breastfeed a baby while on this study. Also check with 
your doctor about how long you should not breastfeed after you stop the study 
treatment(s). 
 
Risks of Study 
The use of palbociclib instead of another treatment may cause more complications.          
 
Your other treatment options may include: 
• 
Getting treatment or care for your cancer without being in a study 
• 
Taking part in another study 
• 
Focusing on comfort care instead of drugs to treat the tumor 
  
The palbociclib plus chemotherapy treatment that is being studied could be less effective than 
another treatment. 
 
You may lose time at school, work or home and spend more time in the hospital or doctor’s 
office than usual. You may be asked sensitive or private questions which you normally do not 
discuss.  
 
The chemotherapy used in this study may affect how different parts of your body work such as 
your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug/study approach. 
 
Here are important points about side effects: 
• 
The study doctors do not know who will or will not have side effects. 
• 
Some side effects may go away soon, some may last a long time, or some may never go 
away. 


 
 
 
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• 
Some side effects may interfere with your ability to have children. 
• 
Some side effects may be serious and may even result in death. 
 
You can ask your study doctor questions about side effects at any time.  
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• 
Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• 
The study doctor may be able to treat some side effects. 
• 
The study doctor may adjust the study drugs to try to reduce side effects. 
• 
The study doctor will provide you with information about other drugs you may need to 
avoid while receiving the study drugs. 
 
There might be other side effects that researchers do not yet know about. If important new side 
effects are found, the study doctor will discuss these with you. 
 
There may be unknown risks, or risks that we did not anticipate, associated with being in this 
study. 
 
Are there benefits to taking part in the study? 
 
We hope that this study will help you personally, but we do not know if it will.  
 
Potential benefits to you could include:  
• 
May cause your ALL or LL to stop growing or to go into remission for a period of time 
• 
May lesson the symptoms that are caused by the ALL or LL. 
 
With any cancer treatment, sometimes treatment does not make the cancer go away. Or, 
sometimes treatment makes the cancer go away for a while but the cancer comes back later. 
 
We expect that the information learned from this study will benefit other patients in the future.  
 
What other options are there? 
 
Instead of being in this study, you have these options: 
 
• 
Getting treatment for your cancer without being in a study 
• 
Taking part in another study. 
• 
Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly. Instead it tries to improve how you feel. Comfort care tries to keep you as 
active and comfortable as possible. 
 
Please talk to your doctor about these and other options. 
 
How many people will take part in the study? 
 
The total number of people enrolled on this study is expected to be 30 patients.  


 
 
 
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How long is the study? 
 
People in this clinical trial are expected to receive treatment on this study for about 42 Days. After 
treatment, you will have follow-up examinations and medical tests. 
 
We would like to continue to find out about your health for about 30 days after your last day of 
receiving cancer fighting medicine on this study. By keeping in touch with you for a while after you 
complete treatment, we can better understand the long-term effects of the study treatments. 
 
You can stop taking part in the study at any time. However, if you decide to stop participating in 
the study, we encourage you to talk to the study doctor and your regular doctor first. They will 
help you stop safely.  
 
Your doctor or the study doctor may decide to take you off this study: 
• 
if he/she believes that it is in your best interest 
• 
if your disease does not respond to the treatment or gets worse 
• 
if you experience side effects from the treatment that are considered too severe 
• 
if new information becomes available that shows that another treatment would be better for 
you 
• 
if you are female and become pregnant 
 
What about privacy? 
 
We will do our best to make sure that the personal information in your medical record will be kept 
private. If information from this study is published or presented at scientific meetings, your name 
and other personal information will not be used. The Children’s Oncology Group has a privacy 
permit to help protect your records if there is a court case. However, some of your medical 
information may be given out if required by law. If this should happen, the Children’s Oncology 
Group will do their best to make sure that any information that goes out to others will not identify 
who you are. Information about this Certificate of Confidentiality is included in Attachment 3. 
 
Organizations that may look at and/or copy your research or medical records for research, 
quality assurance and data analysis include groups such as: 
 
• 
Children's Oncology Group and research partners 
• 
Representatives of government agencies, such as the Food and Drug Administration 
(FDA), and other U.S. and international governmental regulatory agencies involved in 
overseeing research. 
• 
The Institutional Review Board of this hospital 
• 
The drug company supporting the study (the company that make palbociclib) or their 
designated reviewers.  
  
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy. The goal of this data 
sharing is to make more research possible that may improve people’s health. Your study records 
may be stored and shared for future use in public databases. However, your name and other 
personal information will not be used.   
 


 
 
 
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Some types of future research may include looking at your information and information from other 
patients to see who had side effects across many studies or comparing new study data with older 
study data. However, right now we don’t know what research may be done in the future using 
your information. This means that:  
 
• 
You will not be asked if you agree to take part in the specific future research studies using 
your health information. 
• 
You and your study doctor will not be told when or what type of research will be done. 
• 
You will not get reports or other information about any research that is done using your 
information.  
 
 
What are the costs? 
 
Taking part in this study may lead to added costs to you or your insurance company. There are 
no plans for the study to pay for medical treatment. Please ask about any expected added costs 
or insurance problems. Staff will be able to assist you with this. 
 
In the case of injury or illness resulting from this study, emergency medical treatment is available 
but will be provided at the usual charge. No funds have been set aside to compensate you in the 
event of injury. However by signing this form, you are not giving up any legal rights to seek to 
obtain compensation for injury. 
 
You or your insurance company will be charged for continuing medical care and/or hospitalization.  
 
The drug company will provide palbociclib at no charge while you take part in the study.  The drug 
company does not cover the cost of getting the palbociclib ready and giving it to you, so you or 
your insurance company may have to pay for this. Costs associated with the intensive reinduction 
chemotherapy must be covered by you or your insurance company. 
 
Even though it probably won’t happen, it is possible that the study may not be able to continue to 
provide the palbociclib for some reason.  If this should occur, other possible options are: 
• 
You might be able to get the palbociclib from the manufacturer or your pharmacy but you 
or your insurance company may have to pay for it. 
• 
If there is no palbociclib available at all, no one will be able to get more and the study 
would close.   
 
If a problem with getting palbociclib occurs, your study doctor will talk to you about these options.  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://www.cancer.gov/clinicaltrials/learningabout. 
 
You will not be charged for the costs of the special biology studies that are being done 
for research purposes only. 
 
Funding support 
 
If you choose to enroll on this study, this institution will receive some money from the Children’s 
Oncology Group to do the research. There are no plans to pay you for taking part in this study. 


 
 
 
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The drug company that makes palbociclib is providing money to the Children’s Oncology Group 
to do the research. 
 
Money to do this research is also being provided by the Children’s Oncology Group Foundation.   
 
This study includes providing specimens to the researcher, there are no plans for you to profit 
from any new product developed from research done on your specimens.  
 
What are my rights as a participant? 
 
Taking part in this study is voluntary. You may choose not to be in this study. If you decide not to 
be in this study, you will not be penalized and you will not lose any benefits to which you are 
entitled. You will still receive medical care.  
 
You can decide to stop being in the study at any time. Leaving the study will not result in any 
penalty or loss of benefits to which you are entitled. Your doctor will still take care of you. 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay 
in this study. A committee outside of COG closely monitors study reports and notifies COG if 
changes must be made to the study. Members of COG meet twice a year to discuss results of 
treatment and to plan new treatments.  
 
 
Whom do I call if I have questions or problems? 
 
For questions about the study or if you have a research related problem or if you think you have 
been injured in this study, you may contact Dr. XXXX or your doctor at XXXX. 
 
If you have any questions about your rights as a research participant or any problems that you 
feel you cannot discuss with the investigators, you may call XXXX Institutional Review Board 
(IRB) Administrator at XXXX. 
 
If you have any questions or concerns that you feel you would like to discuss with someone who 
is not on the research team, you may also call the Patient Advocate at XXXX. 
 
Where can I get more information? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources. Your 
doctor can get you this Handbook, or you can get it at:  
 https://www.childrensoncologygroup.org/index.php/cog-family-handbook. 
 
Visit the NCI's Web site at http://www.cancer.gov. 
 
If you are in the United States, you may call the NCI's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237).  
 
Information about long term follow-up after cancer treatment can be found at: 
http://www.survivorshipguidelines.org/. 


 
 
 
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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at 
any time. 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
Specimens for optional research tests 
 
The choice to let us use specimens for research is up to you. No matter what you decide to do, 
it will not affect your care. You can still be a part of the main study even if you say ‘No’ to taking 
part in any of these optional research studies. 
 
If you decide that your specimens can be used for research, some health information may be 
placed in central databases for researchers to use.  The databases will not include your name 
or contact information.   
 
If you decide now that your specimens can be used for research, you can change your mind at 
any time. Just contact us and let us know that you do not want us to use your specimens. Then, 
any specimens that we have will be destroyed.  
 
The most common risks related to drawing blood from your arm are brief pain and maybe a 
bruise.   
 
Please read the information below and think about your choices. After making your decisions, 
check “Yes” or “No”, then add your initials and the date after your answer. If you have any 
questions, please talk to your doctor or nurse, or call our research review board at the IRB’s 
phone number included in this consent. 
 
1.) My blood may be sent to a research laboratory and studied to see the effects of 
palbociclib on leukemia cells, the tests may help us to better learn how this drug 
may work. 
  
Yes_____  
No_____  
________ / _______ 
 Initials  
Date 
 
2.) My bone marrow may be sent to a research laboratory and studied to see the 
effects of palbociclib on leukemia cells, the tests may help us to better learn how 
this drug may work. 
  
Yes_____  
No_____  
________ / _______ 
 Initials  
Date 
 
 
 
 
 
 
 


 
 
 
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Signature 
 
I have been given a copy of all 23 pages of this form. The form includes three (3) 
attachments.  
 
I have reviewed the information and have had my questions answered.  
I agree to take part in this study. 
 
Participant 
Date  
 
 
Parent/Guardian 
Date  
 
 
Parent/Guardian 
Date  
 
 
Physician/PNP obtaining consent 
Date  
  


 
 
 
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Attachment 1 
 
Treatment and Procedures Common to all Patients with ALL or LL 
 
Methods for Giving Drugs  
Various methods will be used to give drugs: 
• 
PO - Drug is given by tablet or liquid swallowed through the mouth. 
• 
IV - Drug is given using a needle or tubing inserted into a vein. Drugs can be given rapidly 
over a few minutes (“push”) or slowly over minutes or hours (“infusion”). 
• 
IT - Drug used to treat the brain and spinal cord is given using a needle inserted through the 
back into the fluid surrounding the spinal cord. 
 
Central Line 
Your doctor may recommend that you get a special kind of IV called a “central line.” This is a kind 
of IV placed into a big vein in your body, usually in the chest, that can stay in for a long time. The 
risks connected with central lines will be explained to you and all of your questions will be 
answered. If you are to have a central line inserted, you will be given a separate informed consent 
document to read and sign for this procedure. A description of the types of central lines is in the 
COG Family Handbook for Children with Cancer. 
 
Lumbar Punctures (“L.P.s”, “spinal taps”) 
You are familiar with spinal taps since they were done during your (your child’s) initial therapy for 
ALL. Whether you decide to (allow your child to) participate or not on this study, additional spinal 
taps will need to be done to prevent the leukemia from spreading to the spinal fluid. Spinal taps 
are painful and may cause headaches. The skin at the site of needle insertion is usually numbed 
with an anesthetic cream or lidocaine before the procedure is performed. Approximately 1 
teaspoon of spinal fluid will be withdrawn prior to injection of the medicines (cytarabine or 
methotrexate alone, or the combination of methotrexate, cytarabine and hydrocortisone, if 
leukemia is present in the spinal fluid or brain). 
 
During the study you will have tests and procedures to check for side effects and see how your 
tumor is doing. These tests are part of regular cancer care, but you may have them more often 
because you are on the study. Copies of the scans used to diagnose your cancer and some of 
the tissue already taken may be sent to a central review center as part of COG quality control. 
COG does this to double check the hospitals’ results. 
 
Standard Tests and Procedures 
The following tests and procedures are part of regular cancer care and may be done even if you 
do not join the study.  
 
• 
Urine tests to measure how your kidneys are functioning. 
• 
Pregnancy test for females of childbearing age before treatment begins. 
• 
X-rays and scans to monitor your response to treatment. 
• 
Tests to monitor your heart and lung function. 
• 
Bone marrow aspiration tests to see if the cancer is responding to treatment. The bone marrow 
procedure is described in the COG Family Handbook for Children with Cancer. 
• 
Spinal Taps to check for cancer cells in the spinal fluid and to give chemotherapy into the 
spinal fluid. This is described in the COG Family Handbook for Children with Cancer. 
• 
Blood tests 
• 
Physical Exam 
 


 
 
 
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Attachment 2 
 
Risks of Chemotherapy Drugs Used to Treat ALL or LL 
 
Possible Side Effects of Asparaginase Erwinia 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Asparaginase Erwinia, more than 20 and up to 100 may have: 
• Nausea 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Asparaginase Erwinia, from 4 to 20 may have: 
• Pain in belly 
• Vomiting 
• Blood clot 
• Fever 
 
RARE, AND SERIOUS 
In 100 people receiving Asparaginase Erwinia, 3 or fewer may have: 
• Diarrhea 
• Bleeding 
• Seizure 
 
Possible Side Effects of Cytarabine (ara-c) when given into the spinal fluid 
(intrathecal) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving cytarabine (ara-c) when given into the spinal fluid, more than 20 
and up to 100 may have: 
• Nausea, vomiting 
• Fever 
• Headache 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving cytarabine (ara-c) when given into the spinal fluid, from 4 to 20 
may have: 
• Anemia which may cause tiredness, or may require blood transfusions 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Tiredness, dizziness, loss of coordination 
• Numbness and tingling of the arms and legs  
• Inflammation of the lining of the brain that can lead to headache, numbness and 
tingling 
 


 
 
 
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RARE, AND SERIOUS 
In 100 people receiving cytarabine (ara-c) when given into the spinal fluid, 3 or fewer may 
have: 
• Seizure 
• Paralysis  
• Blurred vision with a chance of blindness 
• Damage to the brain that may result in a decrease in the ability to learn  
 
Possible Side Effects of Doxorubicin  
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Doxorubicin, more than 20 and up to 100 may have: 
• Hair loss 
• Vomiting 
• Red colored urine, saliva, or sweat  
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Doxorubicin, from 4 to 20 may have: 
• Heart failure or heart attack which may cause shortness of breath, swelling of 
ankles, cough or tiredness which may occur years after the dose 
• Abnormal heartbeat 
• Damage to the lungs which may cause shortness of breath when combined with 
radiation  
• Infection, especially when white blood cell count is low  
• Bruising, bleeding 
• Anemia which may cause tiredness, or may require transfusion 
• Hepatitis or damage to the liver which may cause yellow eyes and skin, swelling 
• Kidney damage which may require dialysis 
• Swelling and redness at the site of the medication injection or area of previous 
radiation 
• Belly pain 
• Sores in the mouth or throat 
• Nausea, diarrhea 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat 
• Damage to the skin which may cause pain 
• Cancer of the bone marrow (leukemia) caused by chemotherapy 
• Darkening of the nail beds or skin or hands and feet 
• Loss of nails 
 
RARE, AND SERIOUS 
In 100 people receiving Doxorubicin, 3 or fewer may have: 
• Severe blood infection 
 
 
 
 


 
 
 
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Possible Side Effects of Intrathecal Triples (cytarabine, methotrexate, and 
hydrocortisone) when given into the spinal fluid  
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving intrathecal triples, more than 20 and up to 100 may have: 
• Nausea, vomiting 
• Fever 
• Headache 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving intrathecal triples, from 4 to 20 may have: 
• Swelling of the brain which may cause blurred vision and/or confusion 
• Damage to the brain which may cause changes in thinking 
• Difficulty with speaking  
• Pain 
• Confusion, dizziness 
• Tiredness 
• Rash 
 
RARE, AND SERIOUS 
In 100 people receiving intrathecal triples, 3 or fewer may have: 
• Seizure  
• Damage to the brain which could lead to coma 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat 
• Bleeding into the space of the spine at the site of the injection  
• Paralysis, weakness 
• Infection  
 
Possible Side Effects of Methotrexate when given into the spinal fluid (intrathecal) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving methotrexate when given into the spinal fluid, more than 20 and 
up to 100 may have: 
• Nausea 
• Headache 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving methotrexate when given into the spinal fluid, from 4 to 20 may 
have: 
• Swelling of the brain which may cause blurred vision, and/or confusion 
• Damage to the brain which may cause changes in thinking 
• Confusion, dizziness 
• Vomiting 
• Rash 
• Tiredness 
• Pain 
• Anemia which may require blood transfusions 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Difficulty with speaking 
RARE, AND SERIOUS 
In 100 people receiving methotrexate when given into the spinal fluid, 3 or fewer may 
have: 
• Seizure 
• Damage to the brain which could lead to coma 
• Paralysis, weakness 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat  
• Bleeding into the space of the spine at the site of the injection 
 
Possible Side Effects of Pegaspargase  
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Pegaspargase, more than 20 and up to 100 may have: 
• Nausea, vomiting 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat  
• Chills, fever 
• Tiredness 
• Hives, rash 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Pegaspargase, from 4 to 20 may have: 
• Blood clot 
• Liver damage which may cause yellowing of eyes and skin 
• Anemia which may require blood transfusions 
• Infection, especially when white blood cell count is low 
• Abnormal heart beat 
• Bruising, bleeding 
• Night sweats 
• Headache 
 


 
 
 
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RARE, AND SERIOUS 
In 100 people receiving Pegaspargase, 3 or fewer may have: 
• Belly pain, damage to the pancreas 
 
 
    Possible Side Effects of Prednisone or Prednisolone 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving prednisone or prednisolone, more than 20 and up to 100 may 
have: 
• In children and adolescents: decreased height 
• Loss of bone tissue 
• Mood swings 
• Skin changes, acne 
• Swelling of the body, tiredness, bruising 
• High blood pressure which may cause headaches, dizziness, blurred vision 
• Pain in belly 
• Increased appetite and weight gain in the belly, face, back and shoulders 
• Difficulty sleeping 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving prednisone or prednisolone, from 4 to 20 may have: 
• Blood clot which may cause swelling, pain, shortness of breath 
• Cloudiness of the eye, visual disturbances, blurred vision 
• Glaucoma 
• Infection 
• Non-healing wound 
• Diabetes 
• A tear or a hole in the bowels which may cause belly pain or that may require 
surgery 
• Damage to the bone which may cause joint pain and loss of motion 
• Numbness and tingling of the arms, legs and upper body 
• Muscle weakness 
• Kidney stones 
• Heartburn 
 
RARE, AND SERIOUS 
In 100 people receiving prednisone or prednisolone, 3 or fewer may have: 
• Bleeding from sores in the stomach 
• Broken bones 
 
 
 
 
 
 
 
 


 
 
 
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  Possible Side Effects of Vincristine  
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving vincristine, more than 20 and up to 100 may have: 
• Constipation, nausea, vomiting 
• Hair loss 
• Pain or redness at the site of injection 
• Numbness and tingling of fingers or toes 
• Headache, jaw pain and/or muscle pain 
• Weakness and difficulty walking 
• Swelling of lower legs 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving vincristine, from 4 to 20 may have: 
• Swelling that may be accompanied by confusion, and dizziness 
• Paralysis, weakness, headache, confusion 
• Drooping eyelids 
• Hoarseness 
• Visual loss 
• Difficulty with balance and hearing 
 
RARE, AND SERIOUS 
In 100 people receiving vincristine, 3 or fewer may have: 
• Seizure 
 
 
 


 
 
 
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Attachment 3 
 
Certificate of Confidentiality 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the 
federal government, which will help us protect the privacy of our research subjects. The 
Certificate protects against the involuntary release of information about subjects collected 
during the course of our covered studies. The researchers involved in the studies cannot 
be forced to disclose the identity or any information collected in the study in any legal 
proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings. However, the subject or the researcher may 
choose to voluntarily disclose the protected information under certain circumstances. For 
example, if the subject or his/her guardian requests the release of information in writing, 
the Certificate does not protect against that voluntary disclosure. Furthermore, federal 
agencies may review our records under limited circumstances, such as a DHHS request 
for information for an audit or program evaluation or an FDA request under the Food, Drug 
and Cosmetics Act. 
The Certificate of Confidentiality will not protect against the required reporting by hospital 
staff of information on suspected child abuse, reportable communicable diseases, and/or 
possible threat of harm to self or others.