A Phase I Trial of Palbociclib in Combination With Dexamethasone in Relapsed or Refractory Adult B-Cell Acute Lymphoblastic Leukemia (ALL)
Phase: PHASE1
Conditions: Recurrent B Acute Lymphoblastic Leukemia, Refractory B Acute Lymphoblastic Leukemia
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University

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THOMAS JEFFERSON UNIVERSITY 
Sidney Kimmel Cancer Center 
 
A Phase I Trial of Palbociclib in Combination with Dexamethasone in Relapsed or 
Refractory Adult B-Cell Acute Lymphoblastic Leukemia (ALL) 
 
Principal Investigator: 
Margaret Kasner, MD, MSCE 
Medical Oncology 
834 Chestnut St. Suite 315 
Philadelphia, PA 19107 
215-955-3202 
Co-Investigator(s): 
Lindsay Wilde, MD 
Ubaldo Martinez Outschoorn, MD 
Dolores Grosso, DNP 
Neal Flomenberg, MD 
Joanne Filicko-O’Hara, MD 
Matthew Carabasi, MD 
John Wagner, MD 
Neil Palmisiano, MD 
S. Onder Alpdogan, MD 
Thomas Klumpp, MD 
Pierluigi Porcu, MD 
Kaitlin Rancani, CRNP 
 
Non-Consenting Co-Investigator 
Bruno Calabretta, PhD 
Statistician: 
Benjamin Leiby, PhD 
Division of Biostatistics 
1015 Chestnut St. Suite 520 
215-503-3803 
Funding Sponsor: 
Pfizer Inc. 
IND Holder: 
Margaret Kasner, MD 
IND Number: 
137885 
Study Product: 
Palbociclib (Ibrance®) 
Protocol IDs: 
JeffTrial # 11586 
PRC # 2017-146 
IRB Control # 17P.676 

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Version Number: 
Version Date: 
1.0 
8/10/17 
1.1 
11/29/2017 
1.2 
12/28/2017 
1.3 
03/02/2018 
1.4 
04/13/2018 
2.0 
06/06/2018 
3.0 
12/17/2018 
4.0 
04/19/2019 
5.0 
06/30/2021 
 
CONFIDENTIAL 
This document is confidential and the property of THOMAS JEFFERSON UNIVERSITY. 
No part of it may be transmitted, reproduced, published, or used by other persons 
without prior written authorization from the study sponsor. 
 

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Signature Page .......................................................................................................................... 8 
Statement of Compliance ........................................................................................................... 8 
List of Abbreviations ................................................................................................................... 9 
Study Summary ........................................................................................................................11 
1 
Introduction .........................................................................................................................14 
1.1 
Background Information ..............................................................................................14 
1.2 
Rationale for the Proposed Study ...............................................................................15 
1.3 
Correlative Studies ......................................................................................................15 
1.4 
Potential Risks and Benefits .......................................................................................16 
1.4.1 Potential Risks.........................................................................................................16 
1.4.2 Benefits ...................................................................................................................16 
2 
Study Objectives .................................................................................................................16 
2.1 
Objectives ...................................................................................................................16 
2.1.1 Primary ....................................................................................................................16 
2.1.2 Secondary ...............................................................................................................16 
2.1.3 Exploratory ..............................................................................................................17 
2.2 
Endpoints/Outcome Measures ....................................................................................17 
2.2.1 Primary ....................................................................................................................17 
2.2.2 Secondary ...............................................................................................................17 
2.2.3 Exploratory ..............................................................................................................17 
3 
Study Design ......................................................................................................................17 
3.1 
Characteristics ............................................................................................................18 
3.2 
Number of Participants ...............................................................................................18 
3.3 
Duration of Therapy ....................................................................................................18 
3.4 
Duration of Follow Up .................................................................................................18 

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3.5 
Study Timeline ............................................................................................................18 
3.5.1 Primary Completion .................................................................................................18 
3.5.2 Study Completion ....................................................................................................19 
4 
Study Enrollment and Withdrawal .......................................................................................19 
4.1 
Eligibility Criteria .........................................................................................................19 
4.1.1 Inclusion Criteria ......................................................................................................19 
4.1.2 Exclusion Criteria ....................................................................................................19 
4.2 
Gender/Minority/Pediatric Inclusion for Research........................................................20 
4.3 
Strategies for Recruitment and Retention ...................................................................20 
4.4 
Participant Withdrawal ................................................................................................21 
4.4.1 Reasons for Withdrawal ..........................................................................................21 
4.4.2 Handling of Participant Withdrawals and Participant Discontinuation of Study 
Intervention .........................................................................................................................21 
4.5 
Premature Termination or Suspension of Study ..........................................................21 
5 
Study Intervention ...............................................................................................................21 
5.1 
Study Product .............................................................................................................21 
5.2 
Study Product Description ...........................................................................................22 
5.2.1 Acquisition ...............................................................................................................22 
5.2.2 Formulation, Packaging, and Labeling .....................................................................22 
5.2.3 Product Storage and Stability ..................................................................................22 
5.3 
Dosage, Preparation, and Administration ....................................................................22 
5.4 
Dose Modifications and Dosing Delays .......................................................................23 
5.5 
Study Product .............................................................................................................25 
5.6 
Study Product Description ...........................................................................................25 
5.6.1 Acquisition ...............................................................................................................25 
5.6.2 Formulation, Packaging, and Labeling .....................................................................25 
5.6.3 Product Storage and Stability ..................................................................................25 

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5.7 
Dosage, Preparation, and Administration ....................................................................25 
5.8 
Dose Modifications and Dosing Delays .......................................................................26 
5.9 
Study Product Accountability ......................................................................................26 
5.10 
Assessing Participant Compliance with Study Product Administration ........................26 
5.11 
Concomitant Medications/Treatments .........................................................................26 
6 
Study Schedule ..................................................................................................................28 
6.1 
Enrollment/Baseline ....................................................................................................28 
6.2 
Treatment Period ........................................................................................................28 
 
6.2.1 Dose Escalation Procedures…………………………………………………………30 
6.3 
End of Treatment Study Procedures ...........................................................................32 
6.4 
Post-treatment/Follow-Up ...........................................................................................32 
6.5 
Withdrawal Visit/Discontinuation of Therapy ...............................................................32 
7 
Study Procedures and Evaluations .....................................................................................32 
7.1 
Study Procedures/Evaluations ....................................................................................32 
7.2 
Laboratory Procedures/Evaluations ............................................................................33 
7.2.1 Clinical Laboratory Evaluations ...............................................................................33 
7.2.2 Special Assays or Procedures .................................................................................33 
7.2.3 Specimen Preparation, Handling, and Storage ........................................................33 
7.2.4 Specimen Shipment ................................................................................................33 
8 
Evaluation of Safety ............................................................................................................33 
8.1 
Specification of Safety Parameters .............................................................................33 
8.1.1 Unanticipated Problems ..........................................................................................34 
8.1.2 Adverse Events .......................................................................................................34 
8.1.3 Serious Adverse Events ..........................................................................................34 
8.2 
Safety Assessment and Follow-Up .............................................................................34 
8.3 
Recording Adverse Events ..........................................................................................35 

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8.3.1 Relationship to Study Intervention ...........................................................................35 
8.3.2 Expectedness ..........................................................................................................35 
8.3.3 Severity of Event .....................................................................................................35 
8.3.4 Intervention .............................................................................................................35 
8.4 
Safety Reporting .........................................................................................................36 
8.4.1 Reporting to IRB ......................................................................................................36 
8.4.2 Reporting to SKCC DSMC ......................................................................................36 
8.4.3 Reporting to Funding Sponsor .................................................................................38 
8.4.4 Reporting to FDA .....................................................................................................38 
9 
Study Oversight ..................................................................................................................39 
10 
Clinical Site Monitoring and Auditing ..............................................................................39 
11 
Statistical Considerations ...............................................................................................39 
11.1 
Study Hypotheses .......................................................................................................39 
11.2 
Analysis Plans ............................................................................................................39 
11.3 
Sample Size Considerations .......................................................................................42 
11.3.1 
Replacement Policy .............................................................................................42 
11.3.2 
Accrual Estimates ................................................................................................42 
11.4 
Exploratory Analysis ...................................................................................................42 
12 
Source Documents and Access to Source Data/Documents ..........................................43 
13 
Quality Control and Quality Assurance ...........................................................................43 
14 
Ethics/Protection of Human Participants .........................................................................44 
14.1 
Ethical Standard .........................................................................................................44 
14.2 
Institutional Review Board ...........................................................................................44 
14.3 
Informed Consent Process ..........................................................................................44 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) ..........................44 
14.5 
Participant Confidentiality............................................................................................44 

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14.6 
Future Use of Stored Specimens and Other Identifiable Data .....................................45 
15 
Data Handling and Record Keeping ...............................................................................45 
15.1 
Data Management Responsibilities .............................................................................45 
15.2 
Data Capture Methods ................................................................................................45 
15.3 
Types of Data .............................................................................................................45 
15.4 
Study Records Retention ............................................................................................45 
15.5 
Protocol Deviations .....................................................................................................46 
16 
Study Finances ...............................................................................................................46 
16.1 
Funding Source ..........................................................................................................46 
16.2 
Conflict of Interest .......................................................................................................46 
16.3 
Participant Stipends or Payments ...............................................................................46 
17 Publication and Data Sharing Policy ....................................................................................46 
18 Literature References ...........................................................................................................47 
SUPPLEMENTAL MATERIALS 
Appendices ...............................................................................................................................50 
APPENDIX A: SCHEDULE OF EVENTS ..................................................................................51 
APPENDIX B: ECOG PERFORMANCE STATUS .....................................................................53 
APPENDIX C: SAMPLE HANDLING, PROCESSING, and STORAGE INSTRUCTIONS ..........54 
 
APPENDIX D: REQUESTING A DOSE ESCALATION………………………………………………56 
APPENDIX E: PFIZER SAE REPORT FORM………………………………………………………...57 
 

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Signature Page 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
Principal Investigator: 
Signed: 
 
Date: 
 
Name: 
Margaret Kasner, MD. MSCE 
Title: 
 
Principal Investigator 
Statement of Compliance 
This study will be conducted in accordance with the International Conference on Harmonisation 
guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), and Thomas Jefferson University research 
policies 
 

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List of Abbreviations 
AE 
ALL 
Adverse Event/Adverse Experience 
Acute Lymphoblastic Leukemia 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PRC 
Protocol Review Committee 
QA 
Quality Assurance 
QC 
Quality Control 

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SAE 
Serious Adverse Event/Serious Adverse Experience 
SDS 
Safety Data Sheet (formerly MSDS; Material Safety Data Sheet) 
SKCC 
Sidney Kimmel Cancer Center 
SOP 
Standard Operating Procedure 
TJU 
Thomas Jefferson University 
UAP 
Unanticipated Problem 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Summary 
Title: 
A Phase I Trial of Palbociclib in Combination with Dexamethasone in 
Relapsed or Refractory Adult B-Cell Acute Lymphoblastic 
Leukemia (ALL) 
Précis: 
This Phase I study will be conducted using a standard 3+3 dose 
escalation design.  The initial cohort of patients will receive a 7-day 
lead-in with palbociclib 100mg daily.  Patients will then undergo 
induction with palbociclib 100mg daily in combination with 
dexamethasone for 4 weeks.  At the completion of cycle 1 (day 28), 
patients will undergo a bone marrow biopsy. If the marrow is empty, 
additional treatment will be held for count recovery.  If there is 
evidence of response (CR, CRi, PR, or SD), patients will proceed to 
maintenance therapy.  Maintenance will consist of 1 week of a 
dexamethasone taper plus palbociclib, followed by 3 weeks of 
palbociclib alone.  A bone marrow biopsy will be obtained at the end 
of the first cycle of maintenance.  If the marrow is empty, additional 
treatment will be held for count recovery.  If there is evidence of 
response (CR, CRi, PR, SD), patients will continue maintenance 
therapy.  Maintenance therapy will continue until disease 
progression, dose limiting toxicity, or availability of an alternative 
therapy.  Patients who are not eligible for maintenance therapy will 
stop palbociclib and undergo a one week dexamethasone taper. 
Objectives: 
 
Primary:  
1. To determine the dose and schedule of the combination of 
palbociclib and dexamethasone in patients with relapsed or 
refractory adult B-Cell ALL 
 
2. To determine the safety and tolerability of the combination of 
palbociclib and dexamethasone in patients with relapsed or 
refractory adult B-Cell ALL 
 
 
Secondary:  
1. To evaluate the activity of palbociclib in combination with 
dexamethasone in patients with relapsed or refractory B-Cell ALL 
 
Exploratory: 
1. To determine the pharmacokinetic properties of palbociclib both 
alone and in combination with dexamethasone 

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2. To measure the on-target effects of palbociclib 
3. To measure the on-target effects of dexamethasone 
4. To measure cell cycle activity 
5. To evaluate cellular proliferation and apoptosis 
 
 
Population: 
Adults age 18 or over with a confirmed diagnosis of relapsed or 
refractory B-Cell ALL; Adequate organ function; ECOG PS 0-2 
 
Phase: 
Phase I 
Number of Sites: 
1, Thomas Jefferson University Hospital 
Description of 
Intervention: 
Palbociclib at a starting dose of 100mg daily with dexamethasone  
Study Duration: 
66 months 
Participant 
Participation 
Duration: 
Until disease progression, dose limiting toxicity, or availability of an 
alternative therapy 
Estimated Time to 
Complete 
Enrollment: 
42 months 

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Schematic of Study Design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 Introduction 
1.1 
Background Information 
Acute lymphoblastic leukemia (ALL) is a rare adult cancer, with approximately 6600 new cases 
diagnosed in 2016 [1].  In contrast to pediatric ALL, where improved understanding of disease 
biology and therapeutics have led to a 5-year event free survival rate of greater than 80%, adult 
ALL continues to have a poor prognosis with long-term disease free survival of only 40-45% [2, 
3].  The prognosis for relapsed or refractory ALL in the adult population is even more grim, with 
a 5-year overall survival of about 10% [4, 5].  These statistics highlight the need for novel 
therapeutic options for these patients. 
The Philadelphia chromosome, derived from the translocation t(9;22)(q34;q11.2) that results in 
the BCR-ABL1 fusion gene, is present in approximately 25-30% of adult ALLs (Ph+ ALL) and is 
considered a high-risk feature [6].  Ph-like ALL is a newer high-risk entity that was first identified 
in children, but is now known to comprise 20-25% of adult ALLs; Ph-like ALL has a gene 
expression profile similar to that of Ph+ ALL, but does not express BCR-ABL1 [7]. Several 
genetic alterations have been identified in Ph-like ALL, however, they all share the common 
feature of activating tyrosine kinase signaling.  Patients with Ph-like ALL generally have a poor 
prognosis, particularly if they are of older age [7].   
c-Myb, the cellular progenitor of the v-Myb oncogene, is a sequence specific DNA-binding 
transcription factor that is highly expressed in immature hematopoietic cells [8].  First identified 
in viruses that cause avian leukemia, c-Myb and its products have been shown to be essential 
in regulating normal hematopoiesis and in influencing leukemogenesis [8, 9]. The importance of 
c-Myb in hematopoiesis was first recognized when c-Myb homozygous null mice were found to 
die at embryonic day 15 due to a failure to convert from fetal to adult erythropoiesis [8, 10].  
Additionally, mouse models have demonstrated that conditional knockdown of the c-Myb gene 
in adult hematopoietic stem cells leads to a cessation of cell growth and differentiation, which 
can be restored with restoration of c-Myb function [10]. 
The c-Myb gene is located on chromosome 6q and is frequently affected in both myeloid and 
lymphoid neoplasms, however, the exact role of c-Myb in ALL is under investigation [11].  A 
preclinical model has demonstrated that knockdown of c-Myb via a doxycycline controllable c-
Myb specific shRNAmir causes cell cycle arrest in pre-B-ALL cells [12].  Furthermore, apoptosis, 
as measured both by PARP cleavage and by downregulation of Bcl-2 (an anti-apoptotic 
protein), was also induced in these cells [12].  A similar study conducted at our institution found 
that Ph+ acute lymphoblastic leukemia cells are dependent on Myb expression for proliferation 
and survival, ex vivo and in immunodeficient mice injected with primary Ph+ ALL cells (De 
Dominici et al, submitted for publication). Likewise, expression of MYB is required for disease 
maintenance in mouse models of p190-190BCR-ABL-induced ALL [11]. 
Analyses have shown that the effects of c-Myb depend on transcriptional regulation of CDK6 
and Bcl-2, which may provide novel therapeutic targets in Ph+ ALL (De Dominici et al, 
submitted for publication).  Both effectors appear to be functionally relevant because c-Myb-
silenced Ph+ ALL cells exhibit Rb-dependent cell cycle arrest and apoptosis, both of which are 

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rescued by ectopic expression of cyclin D3, CDK6, and Bcl-2 expression. Preliminary 
experiments in immunodeficient NOD/SCID/IL-2Rnull (NSG) mice injected with primary Ph+ ALL 
cells and treated with the CDK4/CDK6 inhibitor palbociclib, the Bcl-2 pan-inhibitor sabutoclax, or 
the combination of palbociclib and sabutoclax show that treatment with palbociclib is more 
effective than sabutoclax in suppressing Ph+ ALL in NSG mice and that the 
palbociclib/sabutoclax combination is more effective than either drug alone. Palbociclib is a 
small molecule inhibitor of CDK4 and CDK6 that is currently FDA approved for use with the 
aromatase inhibitor letrozole as first-line treatment in postmenopausal women with metastatic 
breast cancer that is estrogen receptor positive and human epidermal growth factor receptor 2 
negative. 
Glucocorticoids play an integral role in the treatment of ALL.  Dexamethasone has been shown 
to have superior activity compared to prednisone and is the steroid of choice in many treatment 
regimens [13].  Preclinical studies suggest that the enhanced cytotoxic activity of 
dexamethasone may be due to its ability to decrease c-Myb expression in ALL cells [14].  
Furthermore, dexamethasone treatment reduces Bcl-2 levels in ALL cells through a Myb-
dependent mechanism, thereby increasing apoptosis [15].  Dexamethasone resistance in ALL 
has been linked to Myb overexpression and can be overcome by Myb silencing [14, 15].  
Prednisone, a steroid with similar activity to dexamethasone, has been tested in ALL cell lines in 
combination with palbociclib and has shown an additive effect (Calabretta, unpublished data).   
1.2 
Rationale for the Proposed Study 
This study will evaluate the use of palbociclib in conjunction with dexamethasone for the 
treatment of relapsed or refractory ALL.  We will begin giving palbociclib at a dose of 100mg PO 
daily with escalation in increments of 25mg to a maximum dose of 150mg.  Initial Phase I testing 
of palbociclib in patients with advanced solid tumors revealed a maximum tolerated dose (MTD) 
of 125mg daily.  The primary dose limiting toxicity was bone marrow suppression, an important 
consideration when treating sold tumors, but an expected, and possible surrogate marker for 
efficacy, in the treatment of leukemia. Dexamethasone may decrease serum drug levels of 
palbociclib, so we will begin with a palbociclib dose of 100mg and escalate from there.  Dosing 
regimens in ALL vary; in this study, we propose giving dexamethasone at a starting dose of 
20mg daily in conjunction with palbociclib, and then decreasing the dose by 4mg weekly over 4 
weeks to minimize side effects.    
If the combination of palbociclib and dexamethasone is found to be safe and well-tolerated, we 
would hope to move forward with a larger, Phase II study. 
1.3 
Correlative Studies 
The following correlative studies will be performed in the Calabretta Laboratory: 
1. RB phosphorylation (CDK4/6 phosphorylation sites) by Western blot as the primary 
read-out of palbociclib activity. 
2. FOXM1 expression by Western blot as the secondary read-out of palbociclib activity 
(since FOXM1 is a CDK4/6 target) 

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3. RNA isolated from CD19+ cells will be used for gene expression profiles (microarray or 
RNA-Seq) to measure p21 expression as an indicator of cell cycle activity 
4. RNA isolated from CD19+ cells will be used for gene expression profiles (microarray or 
RNA-Seq) to measure S-Phase, Annexin V/Caspase 3 activation as indicators of 
proliferation and apoptosis 
5. RNA isolated from CD19+ cells will be used for gene expression profiles (microarray or 
RNA-Seq) to measure Expression of Myb and Bcl-2 as a read-out of dexamethasone 
sensitivity 
 
These analyses will be performed on pre-treatment samples (peripheral blood and/or bone 
marrow) as well as on day +1 (after 1 week of palbociclib alone) and day +8 (after 1 week of 
combined therapy) of treatment (peripheral blood).   
1.4 
Potential Risks and Benefits 
1.4.1 
Potential Risks 
Patients will be informed of all anticipated and possible unanticipated adverse effects of drug 
treatments. Anticipated treatment-related adverse events include myelosuppression, nausea, 
vomiting, fatigue, diarrhea, anorexia, neutropenic fever, infection, pulmonary embolism, 
hyperglycemia, insomnia, adrenal suppression, myopathy, and psychiatric disturbances. 
Treatment-related mortality can occur from intensive anti-leukemic therapy and is estimated at 
5-10%. Alternative therapies, including standard chemotherapy, investigational agents, and 
supportive care-only, will be discussed with potential patients prior to informed consent.  
1.4.2 
Benefits 
Should the combination of palbociclib and dexamethasone improve complete response rate--a 
surrogate for survival in ALL-- participation would provide substantial benefit for study 
participants. An additional and more certain benefit is the scientific knowledge gained from this 
clinical trial’s correlative studies. This may improve understanding of the pathophysiology of ALL 
and provide insight into additional novel therapies. Although study participants cannot be 
guaranteed benefit, the information gained may benefit cancer patients in the future. 
2 Study Objectives 
2.1 
Objectives 
2.1.1 
Primary 
 
To determine the dose and schedule of the combination of palbociclib and 
dexamethasone in patients with relapsed or refractory adult B-Cell ALL 
 
To determine the safety and tolerability of the combination of palbociclib and 
dexamethasone in patients with relapsed or refractory adult B-Cell ALL 
 
2.1.2 
Secondary 

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 
To evaluate the activity of palbociclib in combination with dexamethasone in patients 
with relapsed or refractory B-Cell ALL 
 
2.1.3 
Exploratory 
 
To determine the pharmacokinetic properties of palbociclib both alone and in 
combination with dexamethasone 
 
To measure the on-target effects of palbociclib 
 
To measure the on-target effects of dexamethasone 
 
To measure cell cycle activity 
 
To evaluate cellular proliferation and apoptosis 
2.2 
Endpoints/Outcome Measures 
2.2.1 
Primary 
 
Dose limiting toxicity and maximum tolerated dose of the combination of palbociclib and 
dexamethasone 
2.2.2 
Secondary 
 
To observe clinically relevant responses to therapy (defined in section 11.2) as 
determined by bone marrow biopsy after cycle 1 
2.2.3 
Exploratory 
 
To evaluate a number of pharmacokinetic and pharmacodynamic biomarkers that 
measure the effect of the combination of palbociclib and dexamethasone including: 
o Plasma levels of palbociclib  
o Western blots of phospho-RB (using antibodies that recognize CDK4/6 
phosphorylation sites on RB) and FOXM1 (CDK4/6 substrate which is stabilized 
by phosphorylation) on lysates from peripheral blood or bone marrow CD19+ 
cells (obtained by FACS sorting).  
o RNA isolated from CD19+ cells will be used for gene expression profiles 
(microarray or RNA-Seq) to measure Myb and Bcl-2 levels 
o RNA isolated from CD19+ cells will be used for gene expression profiles 
(microarray or RNA-Seq) to measure levels of p21, CDK2, and cyclin E as 
markers of cell cycle activity 
o RNA isolated from CD19+ cells will be used for gene expression profiles 
(microarray or RNA-Seq) to measure levels of S-Phase and Annexin V/Caspase 
3 activation as indicators of proliferation and apoptosis 
3 Study Design 
This single arm, Phase I, single institution, dose escalation study will follow a traditional 3+3 
design (See Section 11).Patients who are receiving treatment with steroids at the time of 
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Patients will receive a 1-week lead-in (Day -7 to Day -1) of palbociclib alone at the appropriate 
dose level.  This will be followed by induction with 4 weeks of palbociclib in combination with 
dexamethasone.  Patients will receive dexamethasone 20mg daily from days 1-7, 16mg daily 
from days 8-14, 12mg daily from days 15-21, and 8mg daily from days 22-28.  If a patient 
experiences a DLT as defined in section 6.2.1, the patient will stop the study drugs and come off 
of the trial. At the completion of induction therapy (Day +28), a bone marrow biopsy will be 
performed.  If the marrow is hypoplastic (<10% cellularity), further treatment will be held (up to 4 
weeks from the last day of the induction cycle) to await count recovery. Count recovery will be 
defined as ≥10% cellularity in the bone marrow, neutrophils ≥0.75 x109/L, and a platelet count ≥ 
75 x 109/L. At the time of count recovery a repeat bone marrow biopsy will be performed.  If a 
CR, CRi, PR, or SD is seen, the patient will move to maintenance therapy. 
    
Maintenance will consist of 1 week of palbociclib plus dexamethasone (20mg daily), followed by 
3 weeks of palbociclib alone.  Patients will have a repeat bone marrow biopsy on day +28 of the 
first maintenance cycle with the same parameters for continuation that were used in induction.  
To proceed to subsequent maintenance cycles, the patient must have neutrophils ≥0.75 x109/L 
and a platelet count ≥ 75 x 10
9/L.  If these criteria are not met, treatment will be held (up to 6 
weeks) until count recovery occurs.  Palbociclib will then be resumed with a level -1 dose 
reduction.  Patients will be maintained on maintenance until disease progression, dose limiting 
toxicity, or availability of an alternative therapy. 
 
Patients who do not meet the criteria for maintenance therapy will stop both palbociclib and 
dexamethasone.   
 
3.1 
Number of Participants 
A minimum of 4 and a maximum of 18 patients will be enrolled. 
3.2 
Duration of Therapy 
Initially, patients will receive single agent palbociclib during induction for 
pharmacokinetic/pharmacodynamics (PK/PD) evaluation followed by combination induction 
therapy with palbociclib and dexamethasone.  Patients who do not achieve a CR, CRi, PR, or 
SD after induction therapy will be taken off the study. Patients who achieve a CR, CRi, PR, or 
SD will receive on palbociclib and dexamethasone maintenance until disease progression or 
dose limiting toxicity. Patients who are transplant ineligible at study entry but achieve a CR and 
thus become transplant eligible may come off study and proceed to transplant. Patients who 
achieve stable disease, but not a CR, will be re-consented after 6 cycles to continue on the 
study. 
3.3 
Duration of Follow Up 
Patients will be followed for late toxicities for 1 year following the discontinuation of therapy.  
3.4 
Study Timeline 
3.4.1 
Primary Completion 

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We anticipate that accrual will be complete within 42 months.   
3.4.2 
Study Completion 
The study will be complete 2 years after the enrollment of the last patient (66 months total study 
duration). 
4 Study Enrollment and Withdrawal 
4.1 
Eligibility Criteria 
4.1.1 
Inclusion Criteria 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate in 
the study: 
1. Patients must have histologic evidence of relapsed or refractory B-cell ALL 
2. Patients must be ≥18 years of age 
3. Patients must have an ECOG performance status of 2 or less (see Appendix B) 
4. Ph+ patients must be refractory to or intolerant of standard tyrosine kinase inhibitor therapy. 
5. Patients must be able to consume oral medication. 
6. Patients must have recovered to ≤ Grade 1 or stabilized from the toxic effects of any prior 
chemotherapy (except alopecia). 
7. Required initial laboratory values: CrCL ≥60mL/min/1.73m2 calculated by Cockroft-Gault; total 
bilirubin <1.5xULN; negative serum or urine pregnancy test for women with child-bearing 
potential. 
8. Patients must be able to sign consent and be willing and able to comply with scheduled visits, 
treatment plan, procedures, and laboratory testing. When it is determined by the study 
investigator that a potential research participant is cognitively impaired, a surrogate consent 
from a caregiver or legally-authorized representative will be obtained. Caregiver or legally-
authorized representative will ensure that they comply with the protocol in order for the subject 
to be considered eligible. 
4.1.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
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1. Patients must not have evidence of active CNS disease 
2. Patients must not be receiving any chemotherapy agents (except hydroxyurea). Intrathecal 
methotrexate and intrathecal cytarabine are permissible. 
3. Patients must not be receiving growth factors (G-CSF, GM-CSF), except for erythropoietin. 
4. Patient must not have a concurrent active malignancy for which they are receiving treatment.. 
5. Patients with other severe concurrent disease which in the judgment of the investigator would 
make the patient inappropriate for entry into this study are ineligible. 
6. Patients must not have received any investigational agents within 30 days of study entry 
unless they have exceeded 5 terminal half-lives of the previous study drug used for treatment.7. 
Patients must not be pregnant or breastfeeding. Pregnancy tests must be obtained for all 
females of child-bearing potential within 10 days prior to enrollment. Pregnant or lactating 
patients are ineligible for this study due to the potential human fetal or teratogenic toxicities of 
palbociclib. Males or women of childbearing potential may not participate unless they have 
agreed to use an effective contraceptive method (defined as hormonal contraceptives, 
intrauterine devices, surgical contraceptives, or condoms). 
8. Patients who have uncontrolled infection are not eligible. Patients must have any active 
infections under control. Fungal disease must have been adequately treated for at least 2 weeks 
before study entry. Subjects with bacteremia must have documented negative blood cultures 
prior to study entry. 
9. Patients who are candidates for allogeneic transplantation, have a suitable donor, and are 
willing to undergo transplantation. 
10. Patients who are eligible for and willing to receive treatment with tisagenlecleucel. 
4.2 
Gender/Minority/Pediatric Inclusion for Research  
Patients will not be excluded based on gender, race, or economic status. Pediatric patients will 
not be included in this study. ALL is slightly more common in men with a ratio of 1.2 to 1.0.  
Accrual will be monitored by the MDG quarterly and if the ratio does not reflect the known 
incidence a plan to increase recruitment of women will be made. 
4.3 
Strategies for Recruitment and Retention 
Patients will be recruited from the practice of the Medical Oncology Department of the Thomas 
Jefferson University Hospital.  The patients must be 18 years of age or older. Patients who meet 
eligibility criteria will be invited by their physician to participate in the study. All therapeutic 
options will be discussed with the patient and the patient’s questions will be answered to the 

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patient’s satisfaction. Patients will be asked to read, comment, and ask questions about the 
study and then sign the informed consent form before study procedures take place. 
4.4 
Participant Withdrawal 
4.4.1 
Reasons for Withdrawal 
Patients are free to withdraw from participation in the study at any time upon request. 
An investigator may terminate a study patient’s participation in the study if: 
 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant. 
 
The patient meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. 
 
The patient does not comply with study medications and procedures 
 
The physician determines that ongoing participation would be detrimental to the patient 
 
The patient no longer wishes to participate 
 
Documented disease progression, unless the investigator (in consultation with the 
sponsor) deems that continued treatment is appropriate. 
 
Initiation of a new anti-cancer therapy 
4.4.2 
Handling of Participant Withdrawals and Participant Discontinuation of 
Study Intervention 
Every attempt will be made to follow patients for data collection, including those patients who 
are prematurely withdrawn, have disease progression, or withdraw consent. 
4.5 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to investigator, funding agency, the 
Investigational New Drug (IND) sponsor and regulatory authorities. If the study is prematurely 
terminated or suspended, the principal investigator will promptly inform the IRB and will provide 
the reason(s) for the termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants. 
 
Insufficient adherence to protocol requirements. 
 
Data that is not sufficiently complete and/or evaluable.  

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 
Determination of futility. 
5 Study Intervention 
5.1 
Study Product  
Palbociclib (Ibrance®) 
5.2 
Study Product Description 
Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Cyclin D1 and CDK4/6 are 
downstream of signaling pathways which lead to cellular proliferation. 
5.2.1 
Acquisition 
Palbociclib will be acquired from the manufacturer, Pfizer Inc. 
5.2.2 
Formulation, Packaging, and Labeling 
Ibrance capsules for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a 
kinase inhibitor. The molecular formula for palbociclib is C24H29N7O2. The molecular weight is 
447.54 daltons. The chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-
yl)pyridin-2 yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, and its structural formula is: Palbociclib is 
a yellow to orange powder with pKa of 7.4 (the secondary piperazine nitrogen) and 3.9 (the 
pyridine nitrogen). At or below pH 4, palbociclib behaves as a high-solubility compound. Above 
pH 4, the solubility of the drug substance reduces significantly. Inactive ingredients: 
Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon 
dioxide, magnesium stearate, and hard gelatin capsule shells. The light orange, light 
orange/caramel and caramel opaque capsule shells contain gelatin, red iron oxide, yellow iron 
oxide, and titanium dioxide; and the printing ink contains shellac, titanium dioxide, ammonium 
hydroxide, propylene glycol and simethicone. 
125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed with 
white ink “Pfizer” on the cap, “PBC 125” on the body.  
100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange 
body, printed with white ink “Pfizer” on the cap, “PBC 100” on the body.  
75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, printed 
with white ink “Pfizer” on the cap, “PBC 75” on the body. 
5.2.3 
Product Storage and Stability 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 
86°F). 
5.3 
Dosage, Preparation, and Administration  

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Patients will begin treatment at assigned dose level. Initial dose level is 100mg.  Based on the 
protocol design, additional patients will be enrolled at either 125mg or 150mg.  Patients will 
receive a daily oral dose of palbociclib.  
 
Palbociclib will be dispensed from the Investigational Drug Service (IDS) at TJU. It will be 
dispensed in pill bottle(s) containing a full cycle’s amount of palbociclib. Patients may start a 
cycle as an outpatient and may self-administer doses at home. Patients will be asked to bring 
their pill bottle(s) as well as their pill diary to each visit.  
Qualified personnel who are familiar with procedures that minimize undue exposure to them and 
to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents in an appropriate environment.  
5.4 
Dose Modifications and Dosing Delays 
Patients who experience a dose limiting toxicity (as defined in section 6.2.1) will stop the study 
drugs and come off of the trial. The dose cohort level will be de-escalated to 75mg PO daily if 
dose limiting toxicity occurs in the initial 100mg dose cohort.  
Patients who complete the first cycle of maintenance but require treatment to be held up to 4 
weeks (after the end of the cycle) to achieve count recovery (as defined below), will have 
palbociclib resumed with a level -1 dose reduction.  
 
For this study, count recovery is defined as ≥10% cellularity in the bone marrow, neutrophils 
≥0.75 x109/L, and a platelet count ≥ 75 x 109/L. 
 
Dose Escalation Schedule 
Dose Level 
Dose* 
Palbociclib (mg) 
Dexamethasone 
(mg) 
Level -1 
75 
20 
Level 1 
100 
20 
Level 2 
125 
20 
Level 3 
150 
20 
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) 
rather than as a percentage. 
 

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For patients who remain on maintenance after the first cycle, palbociclib dose modifications will 
be made as follows: 
Hematologic toxicity (except lymphopenia unless associated with clinical events [eg 
opportunistic infection]), according to Common Toxicity Criteria for Adverse Events Version 
4.03: 
Neutropenia: 
Grade 1 or 2: No dosage adjustment required. 
Grade 3: 
Day 1 of cycle: Withhold palbociclib therapy and repeat CBC with differential within 1 
week. When improved to ≤ grade 2, initiate the next cycle at the same dose. If 
recovery from grade 3 neutropenia is prolonged (>2 weeks), or for recurrent 
grade 3 neutropenia on day 1 of subsequent cycles, decrease to next lower 
dose. 
Grade 3 (ANC 500/mm3 to <1,000/mm3) plus fever ≥38.5°C and/or infection at any time: 
Withhold palbociclib treatment until resolved to ≤ grade 2. Resume at the same 
dose.Grade 4 at any time: Withhold palbociclib treatment until resolved to ≤ grade 2. 
After resolution, resume at next lower dose. 
Anemia: 
Grade 1, 2, or 3: No dosage adjustment required 
Grade 4: Withhold palbociclib treatment until resolved to ≤ grade 2. After resolution, 
resume at next lower dose. 
Thrombocytopenia: 
Grade 1 or 2: No dosage adjustment required. 
Grade 3: 
Day 1 of cycle: Withhold palbociclib therapy and repeat CBC with differential within 1 
week. When improved to ≤ grade 2, initiate the next cycle at the same dose. If 
recovery from grade 3 thrombocytopenia is prolonged (>2 weeks), or for 
recurrent grade 3 thrombocytopenia on day 1 of subsequent cycles, decrease to 
next lower dose. 

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Grade 4 at any time: Withhold palbociclib treatment until resolved to ≤ grade 2. After 
resolution, resume at next lower dose. 
Nonhematologic toxicity (according to Common Toxicity Criteria for Adverse Events Version 4): 
Grade 1 or 2: No dosage adjustment required. 
Grade 3 or higher (if persistent despite optimal medical management): Withhold palbociclib 
until symptoms resolve to ≤ grade 1 or ≤ grade 2 (if toxicity is not a safety risk); after 
resolution, resume at the next lower dose. 
During the maintenance phase, dose reductions of palbociclib may be made as many times as 
necessary for toxicity to a minimum dose of 75mg daily.  Patients may also be changed to a 3 
weeks on, 1 week off dosing schedule to minimize toxicity.  Any patient who requires palbociclib 
to be held for >14 days will be considered for discontinuation of the trial. 
 
Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. 
In vivo, palbociclib is a time-dependent inhibitor of CYP3A. Patients will be screened for 
concomitant medications that are metabolized by these enzymes, and the possibility of a drug-
drug interaction will be considered with dose reduction of concomitant medication, as clinically 
indicated. Patients taking concomitant medications that are metabolized by these enzymes will 
not be excluded from the study. 
5.5 
Study Product  
Dexamethasone (Decadron®) 
5.6 
Study Product Description 
Dexamethasone is a synthetic adrenocortical steroid. 
5.6.1 
Acquisition 
Dexamethasone will be billed to patient insurance and handled through the Jefferson outpatient 
pharmacy. 
5.6.2 
Formulation, Packaging, and Labeling 
Dexamethasone tablets, for oral administration, are supplied in, 0.5 mg and 0.75,  mg, 1 mg, 
2mg, 4mg and 6 mg tabs. Inactive ingredients are calcium phosphate, lactose, magnesium 
stearate, and starch. Dexamethasone 0.5 mg also contain D&C Yellow 10 and FD&C Yellow 6. 
Dexamethasone 0.75 mg also contain FD&C Blue 1. 
5.6.3 
Product Storage and Stability 
Store at controlled room temperature 20° to 25°C (68° to 77°F). 
5.7 
Dosage, Preparation, and Administration  

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The dose of dexamethasone will start at 20mg daily and will taper by 4mg each week over the 
course of induction.  During maintenance, patients will receive 20mg of dexamethasone daily for 
7 days.  Patients will receive a daily oral dose of dexamethasone.  
 
Dexamethasone will be dispensed from a commercial outpatient pharmacy. It will be dispensed 
in pill bottle(s) containing a full cycle’s amount of dexamethasone. Patients may start a cycle as 
an outpatient and may self-administer doses at home. Patients will be asked to bring their pill 
bottle as well as their pill diary to each visit.  
 
5.8 
Dose Modifications and Dosing Delays 
During induction, patients will undergo a planned dexamethasone taper as follows: 20mg of 
dexamethasone daily from days 1-7, 16mg of dexamethasone daily from days 8-14, 12mg of 
dexamethasone daily from days 15-21, and 8mg of dexamethasone daily from days 22-28.  
During maintenance, patients will receive dexamethasone 20mg daily from days 1-7 without a 
taper. 
5.9 
Study Product Accountability 
The IDS at TJU will be responsible for the storage, management, and distribution of the study 
drug.  Patients will be asked to return unused medication at the end of treatment or at the time 
of withdrawal from the study. 
5.10 Assessing Participant Compliance with Study Product Administration 
Patients will be given pill diaries and asked to complete it to assess compliance. 
5.11 Concomitant Medications/Treatments 
Patients must not have received any investigational medications within 30 days of study entry 
unless they have exceeded 5 terminal half-lives of the previous study drug used for treatment. 
The following list of medications/treatments will be screened for with potential alteration for the 
concomitant medication (not steroids), but are not exclusionary.  
Aminoglutethimide: Aminoglutethimide may diminish adrenal suppression by corticosteroids.  
Amphotericin B injection and potassium-depleting agents: When corticosteroids are 
administered concomitantly with potassium-depleting agents (e.g., amphotericin B, diuretics), 
patients should be observed closely for development of hypokalemia. In addition, there have 
been cases reported in which concomitant use of amphotericin B and hydrocortisone was 
followed by cardiac enlargement and congestive heart failure.  
Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in 
corticosteroid clearance (see Drug Interactions, Hepatic Enzyme Inducers, Inhibitors and 
Substrates). NDA 11-664/S-062 Page 7  

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Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids may 
produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase 
agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.  
Anticoagulants, oral: Co-administration of corticosteroids and warfarin usually results in 
inhibition of response to warfarin, although there have been some conflicting reports. Therefore, 
coagulation indices should be monitored frequently to maintain the desired anticoagulant effect.  
Antidiabetics: Because corticosteroids may increase blood glucose concentrations, dosage 
adjustments of antidiabetic agents may be required.  
Antitubercular drugs: Serum concentrations of isoniazid may be decreased.  
Cholestyramine: Cholestyramine may increase the clearance of corticosteroids.  
Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur when the 
two are used concurrently. Convulsions have been reported with this concurrent use.  
Dexamethasone suppression test (DST): False-negative results in the dexamethasone 
suppression test (DST) in patients being treated with indomethacin have been reported. Thus, 
results of the DST should be interpreted with caution in these patients.  
Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of arrhythmias due 
to hypokalemia.  
Ephedrine: Ephedrine may enhance the metabolic clearance of corticosteroids, resulting in 
decreased blood levels and lessened physiologic activity, thus requiring an increase in 
corticosteroid dosage.  
Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism of 
certain corticosteroids, thereby increasing their effect.  
Hepatic Enzyme Inducers, Inhibitors and Substrates: Drugs which induce cytochrome P450 3A4 
(CYP 3A4) enzyme activity (e.g., barbiturates, phenytoin, carbamazepine, rifampin) may 
enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be 
increased. Drugs which inhibit CYP 3A4 (e.g., ketoconazole, macrolide antibiotics such as 
erythromycin) have the potential to result in increased plasma concentrations of corticosteroids. 
Dexamethasone is a moderate inducer of CYP 3A4. Co-administration with other drugs that are 
metabolized by CYP 3A4 (e.g., indinavir, erythromycin) may increase their clearance, resulting 
in decreased plasma concentration.  
Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain 
corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. In addition, 
ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal 
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Nonsteroidal anti-inflammatory agents (NSAIDS): Concomitant use of aspirin (or other 
nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal 
side effects. Aspirin should be used cautiously in conjunction with corticosteroids in 
hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of 
corticosteroids.  
Phenytoin: In post-marketing experience, there have been reports of both increases and 
decreases in phenytoin levels with dexamethasone co-administration, leading to alterations in 
seizure control.  
Skin tests: Corticosteroids may suppress reactions to skin tests.  
Thalidomide: Co-administration with thalidomide should be employed cautiously, as toxic 
epidermal necrolysis has been reported with concomitant use. 
6 Study Schedule  
6.1 
Enrollment/Baseline  
Within the twenty-one days prior to the first dose of palbociclib (day -7), patients will sign the 
informed consent document and have a medical history taken as well as a physical exam 
(including neurological exam), vital signs, performance status assessment and review of 
concomitant medications.  Peripheral blood will be drawn for baseline laboratory studies 
including CBC with differential, complete metabolic panel (CMP), liver function tests, 
electrolytes, urate, and glucose, as well as a pregnancy test, if applicable. See Schedule of 
Events in Section 6.2 for more information. During this period, patients may receive 
cytoreductive treatment with hydroxyurea or steroids at the discretion of the treating physician. 
Patients who are receiving cytoreductive treatment with steroids must undergo at least a 24 
hour washout period prior to their first dose of palbociclib.   
 
Patients will require a bone marrow biopsy and aspirate both for diagnostic purposes and for 
pharmacodynamic studies. The baseline bone marrow biopsy/aspirate may be substituted with 
peripheral blood collection for patients with circulating disease only if peripheral blood blasts are 
>200/l (WBC x blast percentage >0.2 thousand/uL).  Subsequent bone marrow biopsies will be 
performed at the completion of induction and the completion of cycle 1 of maintenance. 
6.2 
Treatment Period 
 

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*for the purposes of this study, Day 0 and Day +1 are the same during the induction phase 
 
Induction Phase 
Mandatory study visits will be conducted during the induction period on the following days: 
- 
Day +1 
- 
Day +8 
- 
Day +28 
At each visit, patients will undergo a physical exam, vital signs, and an adverse event 
assessment.  Peripheral blood will be drawn for a CBC with differential, serum chemistry with 
electrolytes, and liver function tests.  On day +1 and day +8 of induction, prior to the 
administration of dexamethasone and palbociclib, patients will have blood drawn for 
pharmacokinetics.  On day +1 and day +8 of induction, prior to the administration of 
dexamethasone, patients will also have blood drawn for pharmacodynamic studies.  A bone 
marrow biopsy will performed to assess for response on day +28. 
Maintenance Phase 
Mandatory study visits will be conducted during the maintenance phase on the following days: 
- 
Day +28 

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At this visit, patients will undergo a physical exam, vital signs, and an adverse event 
assessment.  Peripheral blood will be drawn for a CBC with differential, serum chemistry with 
electrolytes, and liver function tests.  A bone marrow biopsy will performed to assess for clinical 
response on day +28. 
After the first cycle of maintenance, patients will be monitored with peripheral blood studies 
every other week.  Bone marrow biopsy will only be performed if there is suspicion of relapsed 
disease. 
See Appendix A for the Schedule of Events.  
6.2.1 
Dose Escalation Procedures 
 
Dose Escalation Schedule 
Dose Level 
Dose* 
Palbociclib (mg) 
Dexamethasone 
(mg) 
Level -1 
75 
20 
Level 1 
100 
20 
Level 2 
125 
20 
Level 3 
150 
20 
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) 
rather than as a percentage. 
 
The dose escalation portion of this study will enroll within each cohort according to a “3+3 
design”, as explained in the following scheme. Palbociclib will be given as a 1 week lead in 
alone at the appropriate dose level. This will be followed by 4 weeks of Palbociclib in 
combination with dexamethasone (induction phase). Patients will receive dexamethasone 20mg 
daily from days 1-7, 16mg daily from days 8-14, 12mg daily from days 15-21, and 8g daily from 
days 22-28.  Maintenance phase will consist of 1 week of Palbociclib with a dexamethasone 
20mg daily followed by 3 weeks of Palbociclib alone. See Section 5.4 for Palbociclib dose 
modifications/dose levels. 
Patients who experience a DLT during the evaluation period as defined below, will stop the 
study drugs and come off of the trial. 
 
Patients who complete the first cycle of maintenance but require treatment to be held up to 4 
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The dose escalation portion of this study will follow a traditional 3+3 design, escalating to the 
next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of 
therapy. The following will be will be defined as a DLT: 
Toxicity 
DLT Criteria* 
Hematology 
 
Marrow aplasia (defined as <10% cellularity with <10% blasts for ≥ 6 
weeks not attributable to disease) 
 
Grade 4 neutropenia persisting ≥6 weeks from the start of a cycle that 
is not attributable to the underlying disease 
Cardiac 
 Any ≥ Grade 3 toxicity 
Gastro-intestinal  Any ≥ Grade 3 toxicity except: 
 
Grade 3 nausea, vomiting**, or diarrhea** not requiring total parenteral 
nutrition (TPN) or tube-feeding 
Hepato-biliary 
 An increase in AST or ALT >3 x ULN and concurrent increase in total 
bilirubin >2 x ULN (Hy's Law) 
 
Any ≥ Grade 3 toxicity except: 
 
Any Grade 3 or 4 liver abnormalities (AST, ALT, or alkaline 
phosphatase) that resolve to < grade 2 within 72 hours 
 
Grade 3 hyperbilirubinemia that resolves to < grade 2 within 72 hours 
 
Grade 3 indirect hyperbilirubinemia that resolves to < grade 2 within 72 
hours 
Renal 
 Any ≥ Grade 3 toxicity 
Non-
Hematologic 
 ≥ Grade 3, including electrolyte abnormalities, except as noted elsewhere in 
the table 
Exceptions to 
DLT criteria 
 
Grade 3 alopecia 
 
Grade 3 fatigue of < 5 days’ duration 
 
Grade 3 electrolyte abnormalities that last <72 hours  
 
Infection (including neutropenic fever), unless the investigator 
determines that the infection or neutropenic fever resulted from the 
degree or duration of myelosuppression in the absence of persistent 
leukemia  
* CTCAE version 5.0 should be used for grading. 

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** Optimal therapy for vomiting and diarrhea should be based on institutional guidelines with 
consideration of the prohibited medications listed in these protocol guidelines. 
 
The DLT evaluation period is defined as 35 days (one week lead-in plus Cycle 1). In order to be 
considered evaluable, the patient needs to take 80% of the doses in the one week lead-in and 
Cycle 1 (1 cycle=28 days). The 80% completion can be non-consecutive days of dosing with 
study drug within the one week lead-in and Cycle 1. Any DLT will be followed until resolution. 
If one DLT is recorded, then three additional patients will be enrolled into the present cohort. If 
no further DLTs occur (1 out of 6 DLTs) then the next patient will be enrolled in the next higher 
cohort. If 2 out of 6 patients have an observed DLT in any given cohort, 3 additional patients will 
be treated at one dose level lower, and if no additional DLTs are observed, this will be the 
maximum tolerated dose. If no DLTs are observed in all three cohorts then the expansion phase 
dose will be cohort 3 for the expansion phase. Toxicities will be graded according to the 
National Cancer Institute, Common Toxicity Criteria for Adverse Events version 4.0 (NCI 
CTCAE v5.0). If multiple toxicities are seen, the presence of DLT will be based on the most 
severe toxicity experience. 
Once three patients have enrolled onto the dose cohort and the DLT evaluation period or the 
third patient has passed, a meeting will be held with the PI and the TJU Medical Monitor to 
review the safety information. If it is determined safe to open the next dose cohort, a formal 
letter from the Medical Monitor will be issued. Please see Appendix D for more information.  
 
6.3 
End of Treatment Study Procedures 
At the end of treatment, patients will be assessed with a history and adverse event assessment. 
Patients who receive maintenance therapy and achieve a CR will be assessed at the time of 
disease progression with a history, adverse event assessment, and bone marrow biopsy to 
confirm progression. 
6.4 
Post-treatment/Follow-Up 
Patients will be followed every three months for one year after treatment ends for evidence of 
late toxicity.  Follow up visits will either occur as part of routine clinical visits (standard of care) 
or through review of the patient medical record. Patients who were ineligible for transplant at 
study entry but achieve a CR and thus become transplant eligible will be followed.  
6.5 
Withdrawal Visit/Discontinuation of Therapy 
If a patient withdraws early or the investigator terminates a patient’s participation the following 
should still be offered to the patient: 
 
Recording of adverse events 

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 
Recording of physical examination 
 
Recording of compliance with palbociclib and dexamethasone 
7 Study Procedures and Evaluations 
7.1 
Study Procedures/Evaluations 
At enrollment/baseline, each patient will have a medical history.  This will include a review of the 
patient’s medical record.  A medication history will be obtained.  Patients will also undergo a 
physical exam (including neurological exam), vital signs, and performance status assessment.  
7.2 
Laboratory Procedures/Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
Laboratory studies will include a CBC with differential, metabolic panel (creatinine, BUN, 
glucose), magnesium, phosphate, urate, liver function tests (bilirubin, SGOT (AST), SGPT 
(ALT), alkaline phosphatase), and a serum or urine pregnancy test, if applicable. 
7.2.2 
Special Assays or Procedures 
Plasma levels of palbociclib for will be determined by a validated assay performed at PPD in 
Richmond, VA. See Appendix C for full instructions on sample storage, handling, and 
processing for PK/PD analysis.  Palbociclib levels will be obtained within 1 hour prior to dosing 
with dexamethasone and palbociclib on days +1 and +8 of induction.  
For analyses of molecular markers of palbociclib and dexamethasone response, we will perform 
western blots of phospho-RB (using antibodies that recognize CDK4/6 phosphorylation sites on 
RB) and FOXM1 (CDK4/6 substrate which is stabilized by phosphorylation) on lysates from 
peripheral blood or bone marrow CD19+ cells (obtained by FACS sorting). We will also assess 
levels of p21, cyclin E, and CDK2 as markers of cell cycle activity. 
As markers of Dexamethasone response, we will assess MYB and BCL2 levels in pre-treatment 
and post-treatment (palbociclib and dexamethasone combination) CD19+ peripheral blood or 
bone marrow cells. 
For analyses of additional markers of drug response, RNA will be isolated from pre-treatment 
and post-treatment CD19+ cells and used for gene expression profiles (microarray or RNA-
Seq). 
7.2.3 
Specimen Preparation, Handling, and Storage 
Details regarding specimen preparation, handling, and storage for palbociclib PK analysis can 
be found in Appendix C. 

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Details regarding specimen preparation, handling, and storage for PD analyses can be found in 
Appendix C. 
7.2.4 
Specimen Shipment 
Details regarding specimen shipping for palbociclib PK analysis can be found in Appendix C. 
8 Evaluation of Safety 
Patients will be followed for toxicity for one year after the last dose of the study drugs, or until 
resolution of serious adverse events, if one is noted. 
 
8.1 
Specification of Safety Parameters 
8.1.1 
Unanticipated Problems 
Unanticipated problems (UAPs) include, in general, any incident, experience, or outcome that 
meets the following criteria: 
 
unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
UAPs are considered to pose risk to participants or others when they suggest that the research 
places participants or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
These problems are reported to the IRB and are different from, but linked to, regulatory 
reporting required by the FDA. 
8.1.2 
Adverse Events 
An adverse event is any untoward or unfavorable medical occurrence in a human participant, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the participant’s participation in the research, 
whether or not considered related to the participant’s participation in the research. 
8.1.3 
Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
 
Results in death 
 
Is life-threatening (places the participant at immediate risk of death from the event as it 
occurred) 
 
Is disabling or incapacitating 
 
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 
Results in a persistent or significant disability or incapacity 
 
Results in a congenital anomaly or birth defect  
 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the participant or may require intervention to 
prevent one of the outcomes listed in this definition. 
8.2 
Safety Assessment and Follow-Up 
Adverse event reporting will begin after study treatment, unless the AE/SAE is caused by a 
study specific screening procedure, and continue until 30 days (for all AEs and SAEs) after the 
last dose of study treatment or initiation of a new anti-cancer therapy. At each study visit, the 
investigator (or designee) will inquire about the occurrence of AE/SAEs since the last visit. 
Events will be followed for outcome information until resolution or stabilization. 
8.3 
Recording Adverse Events 
The following subsections detail what information must be documented for each adverse event 
occurring during the time period specified in Section 8.2 Safety Assessment and Follow-Up. See 
section 8.4 for reporting details. 
8.3.1 
Relationship to Study Intervention 
The relationship to study intervention or study participation must be assessed and documented 
for all adverse events. Evaluation of relatedness must consider etiologies such as natural 
history of the underlying disease, concurrent illness, concomitant therapy, study-related 
procedures, accidents, and other external factors.  
The following guidelines are used to assess relationship of an event to study intervention: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event onset. 
b. An alternate etiology has been established. 
8.3.2 
Expectedness 

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The PI is responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the intervention. Risk information to assess 
expectedness can be obtained from preclinical studies, the investigator’s brochure, published 
medical literature, the protocol, or the informed consent document. 
8.3.3 
Severity of Event 
Adverse events will be graded for severity according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0.  
8.3.4 
Intervention 
Any intervention implemented to treat the adverse event must be documented for all adverse 
events. 
8.4 
Safety Reporting  
8.4.1 
Reporting to IRB 
8.4.1.1 Unanticipated Problems 
All incidents or events that meet criteria for unanticipated problems (UAPs) as defined in 
Section 8.1.1 Unanticipated Problems require the creation and completion of an unanticipated 
problem report form (OHR-20).  
UAPs that pose risk to participants or others, and that are not AEs, will be submitted to the IRB 
on an OHR-20 form via the eazUP system within 10 working days of the investigator becoming 
aware of the event.  
UAPs that do not pose risk to participants or others will be submitted to the IRB at the next 
continuing review.  
8.4.1.2 Adverse Events  
Grade 1 AEs will be reported to the IRB at continuing review.  
Grade 2 AEs will be reported to the IRB at the time of continuing review.  
8.4.1.3 Serious Adverse Events  
SAEs will be reported to the IRB on OHR-10 forms via the electronic reporting system (eSAEy) 
according to the required time frames described below. 
Grade 3-4 AEs that are unexpected and deemed to be at least possibly related to the study will 
be reported to the IRB within 2 working days of knowledge of the event. 
Grade 3-4 AEs that are deemed unrelated to the study will be reported to the IRB within 5 
working days.  

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Grade 5 AEs will be reported to the IRB within one working day of knowledge of the event. 
All SAEs will be submitted to the IRB at continuing review, including those that were reported 
previously. 
8.4.2 
Reporting to SKCC DSMC 
All AEs and SAEs, safety and toxicity data, and any corrective actions will be submitted to the 
DSMC per the frequency described in the SKCC DSMP. The report to the SKCC DSMC will 
also include any unanticipated problems that in the opinion of the PI should be reported to the 
DSMC. 
All non-hematologic adverse events will be reported to the DSMC. 
The only hematologic events which will be considered a DLT/AE/SAE for this study are (i) 
marrow aplasia (defined as <10% cellularity with <10% blasts for ≥ 6 weeks not attributable to 
disease) (ii) grade 4 neutropenia persisting ≥6 weeks from the start of a cycle that is not 
attributable to the underlying disease and this will be reported. 
All hematologic grade 5 SAEs will be reported to the DSMC regardless of causality. 
For expedited reporting requirements, see table below:                              
DSMC AE/SAE Reporting Requirements 

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8.4.3 
Reporting to Funding Sponsor 
SAEs, as well as all other safety information at the end of the study or as requested by the 
funding sponsor, will be reported to Pfizer within 24 hours of occurrence by faxing the Pfizer 
SAE Event Form to the Pfizer US Clinical Trial Department at 1-866-997-8322 (Appendix E).  
Serious adverse events and all other safety information as defined below will be collected from 
day -7 of the lead-in period with palbociclib until 28 days after discontinuation.  Safety 
Information is defined as any information from any source containing information such as: 
 
Adverse event or suspicion thereof 
 
Lack of efficacy 
 
Overdose/incorrect dosage (accidental or intentional) 
 
Abuse/misuse (e.g., patients sharing medication) even without resulting adverse reaction 
 
Accidental exposure (e.g., child takes parents medication) 
 
Medication error 
 
Withdrawal reactions 
 
Disease progression/exacerbation of existing disease 
 
Drug-drug/Drug-food interaction 
 
Reports of unexpected benefit 
 
Exposure to drug during pregnancy, where the embryo or fetus may have been exposed 
to medicinal products (either through maternal exposure or transmission of a medicinal 
product via semen following paternal exposure). 
 
Exposure to drug during lactation (including uneventful) 
 
Suspected counterfeit product 
 
Suspected transfer of infectious disease/agent by the medicinal product concerned. 
 
Product complaint report (any deficiencies related to the identity, quality, labeling, 
durability, reliability, efficacy, performance of a medicinal product, suspected counterfeit 
product) 
 
Pediatric use (if not an approved use) 
 
Occupational exposure 
 
Off-label use (if not part of the study design) 
8.4.4 
Reporting to FDA 
For studies conducted under an Investigator IND in the US, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as possible 
and no later than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. Pfizer Inc. will be provided 
with a simultaneous copy of all adverse events filed with the FDA.  
SAEs will be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms will be sent to the FDA at: 
 

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MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/  
 
9 Study Oversight 
In addition to the PI’s responsibility for oversight, study oversight will be under the direction of 
the SKCC’s Data and Safety Monitoring Committee (DSMC). The SKCC DSMC operates in 
compliance with a Data and Safety Monitoring Plan (DSMP) that is approved by the NCI.  
10 Clinical Site Monitoring and Auditing 
Clinical site monitoring and auditing is conducted to ensure that the rights of human participants 
are protected, that the study is implemented in accordance with the protocol and/or other 
operating procedures, and that the quality and integrity of study data and data collection 
methods are maintained. Monitoring and auditing for this study will be performed in accordance 
with the SKCC’s Data and Safety Monitoring Plan (DSMP) developed by the SKCC Data and 
Safety Monitoring Committee (DSMC). The DSMP specifies the frequency of monitoring, 
monitoring procedures, the level of clinical site monitoring activities (e.g., the percentage of 
participant data to be reviewed), and the distribution of monitoring reports. Some monitoring 
activities may be performed remotely, while others will take place at the study site(s). 
Appropriate staff will conduct monitoring activities and provide reports of the findings and 
associated action items in accordance with the details described in the SKCC DSMP. 
11 Statistical Considerations  
11.1 Study Hypotheses 
No formal hypotheses will be tested in this Phase I study. 
11.2 Analysis Plans 
This aim will consist of a Phase I trial of palbociclib to determine the maximum tolerated dose 
(MTD) of palbociclib when given in combination with dexamethasone.  A standard 3+3 dose 
escalation design will be employed:  three dose levels of palbociclib will be explored (100mg, 
125mg, 150mg).  Patients will be treated in cohorts of size three to six and the dosage will be 
escalated if the clinical toxicity is acceptable. 
Patients who experience a DLT during the evaluation period as defined in section 6.2.1 will stop 
the study drugs and come off of the trial. 
 

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Patients who complete the first cycle of maintenance but require treatment to be held up to 4 
weeks to achieve count recovery, will have palbociclib resumed with a level -1 dose reduction.  
A dose-limiting toxicity (DLT) is defined in the table below: 
Toxicity 
DLT Criteria* 
Hematology 
 
Marrow aplasia (defined as <10% cellularity with <10% blasts for ≥ 6 
weeks not attributable to disease) 
 
Grade 4 neutropenia persisting ≥6 weeks from the start of a cycle that 
is not attributable to the underlying disease 
Cardiac 
 Any ≥ Grade 3 toxicity 
Gastro-intestinal  Any ≥ Grade 3 toxicity except: 
 
Grade 3 nausea, vomiting**, or diarrhea** not requiring total parenteral 
nutrition (TPN) or tube-feeding 
Hepato-biliary 
 An increase in AST or ALT >3 x ULN and concurrent increase in total 
bilirubin >2 x ULN (Hy's Law) 
Any ≥ Grade 3 toxicity except: 
 
Any Grade 3 or 4 liver abnormalities (AST, ALT, or alkaline 
phosphatase) that resolve to < grade 2 within 72 hours 
 
Grade 3 hyperbilirubinemia that resolves to < grade 2 within 72 hours  
 
Grade 3 indirect hyperbilirubinemia that resolves to < grade 2 within 72 
hours 
 
Renal 
 Any ≥ Grade 3 toxicity 
Non-
Hematologic 
 ≥ Grade 3, except as noted elsewhere in the table 
Exceptions to 
DLT criteria 
 
Grade 3 alopecia 
 
Grade 3 fatigue of < 5 days’ duration 
 
Grade 3 electrolyte abnormalities that last <72 hours 
 
Infection, unless the investigator determines that the infection resulted 
from the degree or duration of myelosuppression in the absence of 
persistent leukemia  
* CTCAE version 5.0 should be used for grading. 
** Optimal therapy for vomiting and diarrhea should be based on institutional guidelines with 
consideration of the prohibited medications listed in these protocol guidelines. 

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The design is constructed to reduce the chance of escalating the dose when the probability of 
DLT is high, and increase the chance of escalating the dose when the probability of DLT is low.  
The maximum tolerated dose (MTD) is defined as the highest dose level where a DLT occurs in 
at most one out of six patients treated.  The escalation scheme is as follows: 
(1) If none of the initial three patients in a cohort experiences a DLT, then a new cohort of three 
patients will be treated at the next higher dose level. 
(2) If one of the three patients in a cohort experiences a DLT, then up to three additional 
patients will be treated at the same dose.  Escalation will continue if only one of six patients 
experiences DLT. 
(3) If two or more patients in a cohort experience DLT, then the MTD will have been exceeded, 
and no further dose escalation will occur.  The previous dose level will be considered the MTD. 
(4) If only three patients were treated at a dose level under consideration as the MTD, then up 
to three additional patients will be accrued.  If no more than one of the six patients at that dose 
level experience a DLT, then that dose level will be confirmed as the MTD.  If two or more 
patients in that cohort experience DLT, then the previous dose level will be studied in the same 
fashion.  
The MTD is defined as the highest dose studied for which the observed incidence of DLT is less 
than 33%.  Frequencies of toxicities will be tabulated according to the NCI Common Toxicity 
Criteria.  Patients will be continued to be followed for one year for evidence of late toxicity. 
 
 
Table 1.1 below gives the probabilities of dose escalation based on true DLT risk in the 3+3 
design. 
                                           True DLT rate 
 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability 
of 
escalation 
 
0.91 
 
0.71 
 
0.49 
 
0.31 
 
0.17 
 
0.08 
 
0.03 
 
0.01 
 
0.001 
 
All patients treated with at least one dose will be included in the safety analysis.   
Response criteria for the study are defined as follows: 
Response Criteria  
Complete Remission (CR) 
No lymphoblasts in the bone marrow 
Absolute neutrophil count ≥0.75 x109/L  

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Platelet count ≥75 x 109 /L 
 
 Complete Remission with Incomplete Hematologic Recovery (CRi) 
<5% lymphoblasts in the bone marrow 
 
 Partial Remission (PR) 
All criteria for CR are satisfied except there are between 5% and 25% lymphoblasts in 
the bone marrow 
 
Stable Disease (SD) 
Failure to achieve at least a PR, but with no evidence of progression as defined as an 
increase of peripheral blood or bone marrow blasts of more than 10% from nadir during 
study.  
 
Progressive Disease (PD) 
For patients with < 5% blasts at baseline, there must be an increase to ≥ 10% blasts.  
For patients with 5% to 10% blasts at baseline, there must be a ≥ 50% increase to > 
10% blasts.  
For patients with 10% to 20% blasts at baseline, there must be a ≥ 50% increase to ≥ 
20% blasts.  
Response rate defined as the proportion of patients who achieve a CR, CRi, PR, or SD  
response will be estimated along with a 95% confidence interval.  
11.3 Sample Size Considerations 
This traditional 3+3 dose escalation study will include a minimum of 4 and a maximum of 24 
participants. The minimum sample size of 4 would be achieved if ≥ 2 patients out of the first 3 
patients have a DLT at dose levels 1 and -1. The maximum sample size of 18 would be 
achieved if 6 patients are enrolled at dose levels -1 through 3 (100 mg, 125mg, 150mg, 175mg).  
The anticipated sample size is 12-18.   
11.3.1 Replacement Policy 
Patients need to take 80% of doses in the one week lead-in and Cycle 1 to be evaluable for 
DLTs. The 80% completion can be non-consecutive days of dosing with study drug within the 
one week lead-in and Cycle.  If a patient is not considered evaluable for DLTs, they must be 
replaced for the purposes of dose escalation. 
11.3.2 Accrual Estimates 
We estimate that we will be able to complete accrual within 42 months. 
11.4 Exploratory Analysis 
Analysis of exploratory endpoints will be descriptive with continuous variables summarized 
using means, medians, standard deviations, and ranges, and categorical variables summarized 
using frequencies and percentages.  The analyses will occur at the conclusion of the trial.  

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Plasma levels of palbociclib will be determined on days 1 and 8 of induction and changes will be 
summarized by dose level.  Phospho-RB and FOXM1 will be assessed by Western blot at days 
1 and 8 of induction. MYB, BCL2, p21, CDK2, cyclin E, S-Phase, Annexin, V/Caspase 3 will be 
assessed by gene expression profiles (microarray or RNA-Seq) on days 1 and 8 of induction. 
12 Source Documents and Access to Source Data/Documents 
Study staff will maintain appropriate medical and research records for this study, in compliance 
with ICH E6, and regulatory and institutional requirements for the protection of confidentiality of 
participant information. Study staff will permit authorized representatives of SKCC and 
regulatory agencies to examine (and when required by applicable law, to copy) research 
records for the purposes of quality assurance reviews, audits, and evaluation of the study 
safety, progress and data validity.  
13 Quality Control and Quality Assurance 
Study staff will maintain appropriate medical and research records for this study, in compliance 
with ICH E6, and regulatory and institutional requirements for the protection of confidentiality of 
participant information. Study staff will permit authorized representatives of SKCC and 
regulatory agencies to examine (and when required by applicable law, to copy) research 
records for the purposes of quality assurance reviews, audits, and evaluation of the study 
safety, progress and data validity.  
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents. Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All missing data must be explained. If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”. If the item is not applicable to the individual case, write “N/A”. All entries should be 
printed legibly in black ink. If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it. All such 
changes must be initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 

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14 Ethics/Protection of Human Participants  
14.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, as drafted by the US National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 
46 and/or the ICH E6.  
14.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented in the study.  
14.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout study participation. Extensive discussion of risks and possible 
benefits of study participation will be provided to participants and their families, if applicable. A 
consent form describing in detail the study procedures and risks will be given to the participant. 
Consent forms will be IRB-approved, and the participant is required to read and review the 
document or have the document read to him or her. The investigator or designee will explain the 
research study to the participant and answer any questions that may arise. The participant will 
sign the informed consent document prior to any study-related assessments or procedures. 
Participants will be given the opportunity to discuss the study with their surrogates or think about 
it prior to agreeing to participate. They may withdraw consent at any time throughout the course 
of the study. A copy of the signed informed consent document will be given to participants for 
their records. The rights and welfare of the participants will be protected by emphasizing to them 
that the quality of their clinical care will not be adversely affected if they decline to participate in 
this study. The consent process will be documented in the clinical or research record.  
14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
Individuals age 18 years or older will not be excluded based on gender, race or economic 
status. 
14.5 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to any study information relating to participants. 

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The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all study 
documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) for the study participants. The clinical study site 
will permit access to such records. 
14.6 Future Use of Stored Specimens and Other Identifiable Data  
No residual specimens will be maintained after the study is complete. 
15 Data Handling and Record Keeping 
The investigators are responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents must be completed in a neat, legible 
manner to ensure accurate interpretation of data. The investigators will maintain adequate case 
histories of study participants, including accurate case report forms (CRFs), and source 
documentation. 
15.1 Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the investigator. All source documents and laboratory reports must be reviewed 
by the study team and data entry staff, who will ensure that they are accurate and complete. 
Unanticipated problems and adverse events must be reviewed by the investigator or designee.  
15.2 Data Capture Methods 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All missing data must be explained. If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”. If the item is not applicable to the individual case, write “N/A”. All entries should be 
printed legibly in black ink. If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it. All such 
changes must be initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
15.3 Types of Data 
Safety, laboratory (clinical, pharmacokinetic, and pharmacodynamic), and outcome data will be 
recorded.  Accrual data will be recorded and will be monitored quarterly by the MDG. 
15.4 Study Records Retention 
Study records will be maintained for at least three years from the date that the grant federal 
financial report (FFR) is submitted to the NIH. 

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Study documents must be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period, however, if required by local regulations. No records will be 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained. 
15.5 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or Manual of Procedures requirements. The noncompliance may be on the part of the 
participant, the investigator, or study staff. As a result of deviations, corrective actions are to be 
developed by the study staff and implemented promptly. 
All deviations from the protocol must be addressed in study participant source documents and 
promptly reported to the IRB and other regulatory bodies according to their requirements  
16 Study Finances 
16.1 Funding Source 
This study will be funded by Pfizer, Inc and Thomas Jefferson University. 
16.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study. All Jefferson University Investigators will follow the TJU Conflicts of 
Interest Policy for Employees (107.03). 
16.3 Participant Stipends or Payments 
Participants will not receive payment for participation in the study. 
17 Publication and Data Sharing Policy  
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial 
as any research project that prospectively assigns human participants to intervention or 

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concurrent comparison or control groups to study the cause-and-effect relationship between a 
medical intervention and a health outcome. Medical interventions include drugs, surgical 
procedures, devices, behavioral treatments, process-of-care changes, and the like. Health 
outcomes include any biomedical or health-related measures obtained in patients or 
participants, including pharmacokinetic measures and adverse events. The ICMJE policy 
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, 
which is sponsored by the National Library of Medicine. Other biomedical journals are 
considering adopting similar policies. The ICMJE does not review specific studies to determine 
whether registration is necessary; instead, the committee recommends that researchers who 
have questions about the need to register err on the side of registration or consult the editorial 
office of the journal in which they wish to publish. 
U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 or FDAAA), 
Title VIII, Section 801 mandates that a "responsible party" (i.e., the sponsor or designated 
principal investigator) register and report results of certain "applicable clinical trials:"  
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations, of a product subject to FDA regulation;  
Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation 
(other than small feasibility studies) and pediatric postmarket surveillance studies. 
NIH grantees must take specific steps to ensure compliance with NIH implementation of 
FDAAA. 
18 Literature References 
1. 
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA: A Cancer Journal for 
Clinicians, 2016. 66(1): p. 7-30. 
2. 
Bassan, R. and D. Hoelzer, Modern Therapy of Acute Lymphoblastic Leukemia. Journal 
of Clinical Oncology, 2011. 29(5): p. 532-543. 
3. 
Stein, A. and S.J. Forman, Allogeneic transplantation for ALL in adults. Bone Marrow 
Transplant, 0000. 41(5): p. 439-446. 
4. 
Gökbuget, N., et al., Outcome of relapsed adult lymphoblastic leukemia depends on 
response to salvage chemotherapy, prognostic factors, and performance of stem cell 
transplantation. Blood, 2012. 120(10): p. 2032-2041. 
5. 
Oriol, A., et al., Outcome after relapse of acute lymphoblastic leukemia in adult patients 
included in four consecutive risk-adapted trials by the PETHEMA Study Group. 
Haematologica, 2010. 95(4): p. 589-596. 
6. 
Chalandon, Y., et al., Randomized study of reduced-intensity chemotherapy combined 
with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood, 2015. 
125(24): p. 3711-3719. 
7. 
Jain, N., et al., Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. 
Blood, 2017. 129(5): p. 572-581. 
8. 
Pattabiraman, D.R. and T.J. Gonda, Role and potential for therapeutic targeting of MYB 
in leukemia. Leukemia, 2013. 27(2): p. 269-277. 

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9. 
O'Rourke, J.P. and S.A. Ness, Alternative RNA Splicing Produces Multiple Forms of c-
Myb with Unique Transcriptional Activities. Molecular and Cellular Biology, 2008. 28(6): 
p. 2091-2101. 
10. 
Lieu, Y.K. and E.P. Reddy, Conditional c-myb knockout in adult hematopoietic stem cells 
leads to loss of self-renewal due to impaired proliferation and accelerated differentiation. 
Proceedings of the National Academy of Sciences, 2009. 106(51): p. 21689-21694. 
11. 
Clappier, E., et al., The <em>C-MYB</em> locus is involved in chromosomal 
translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the 
translocation defining a new T-ALL subtype in very young children. Blood, 2007. 110(4): 
p. 1251-1261. 
12. 
Sarvaiya, P.J., et al., Role of c-Myb in the survival of pre B-cell acute lymphoblastic 
leukemia and leukemogenesis. American Journal of Hematology, 2012. 87(10): p. 969-
976. 
13. 
Inaba, H. and C.-H. Pui, Glucocorticoid use in acute lymphoblastic leukemia: comparison 
of prednisone and dexamethasone. The Lancet Oncology, 2010. 11(11): p. 1096-1106. 
14. 
Sarvaiya, P.J., et al., c-Myb interacts with the glucocorticoid receptor and regulates its 
level in pre-B-acute lymphoblastic leukemia cells(). Molecular and cellular endocrinology, 
2012. 361(1-2): p. 124-132. 
15. 
Jing, D., et al., Opposing regulation of <em>BIM</em> and <em>BCL2</em> controls 
glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells. Blood, 
2015. 125(2): p. 273-283. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendices 
The following documents are officially affiliated with the protocol and will be submitted to the IRB 
as a part of the protocol. As such, changes to these items require a protocol amendment. 
Appendix A: Schedule of Events 
Appendix B: ECOG Performance Status 
Appendix C: Sample Handling, Processing, and Storage Instructions 
Appendix D: Requesting a Dose Escalation/Expansion Approval  
 
 

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APPENDIX A: SCHEDULE OF EVENTS 
 
Baseline 
Induction 
Day+1 
Induction 
Day +410 
Induction 
Day +8  
Induction 
Day +12 10 
Induction 
Days +14 and 
+2110   
Induction 
Day +28 10 
Maintenance 
Cycle 
1 
(weekly) 
Maintenance 
Day +28 10 * 
Maintenance 
Cycles 2-6 
(every other 
week)11 
Follow-up7, 8 
Informed Consent 
X1 
 
 
 
 
 
 
 
 
 
 
Medical/Oncologic History 
X1 
 
 
 
 
 
 
 
 
 
X 
Physical Examination  
(including neurological exam) 
X1 
X 
 
X 
 
 
X 
 
X 
 
 
Vital Signs 
X1 
X 
 
X 
 
 
X 
 
X 
 
 
Performance Status 
X1 
 
 
 
 
 
 
 
 
 
 
Review of concomitant  
medications 
X1 
X 
 
X 
 
 
X 
 
X 
 
X 
Adverse Event Assessment 
 
X 
 
X 
 
 
X 
 
X 
 
X6 
Laboratory Studies 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry, Electrolytes 
X1,7 
X7 
X 
X7 
X 
X 
X7 
X 
X7 
X 
 
Liver Function Tests 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test 
X1,2 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics 
 
X3 
 
X3 
 
 
 
 
 
 
 
Pharmacodynamics 
X3 
X3 
 
X3 
 
 
 
 
 
 
 
Tests & Studies 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Biopsy/Aspirate9 
X1,4 
 
 
 
 
 
X 
 
X 
 
X5 
Investigational Agent 
 
 
 
 
 
 
 
 
 
 
 
Pill Diary Given to Patient 
X1 
 
 
 
 
 
 
 
 
 
 
 
Note: Palbociclib will be given with a one week lead-in starting on Day -7 to Day -1.  
*Patients who continue treatment for multiple cycles will have the maintenance Day +28 
procedures repeated for each cycle. 

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1. To be done within twenty-one days prior to first dose of study drug unless otherwise 
indicated (with exception to the bone marrow biopsy/aspirate which is required at any 
time prior to study treatment). Informed consent, baseline procedures, and confirmed 
eligibility must be completed prior to the one week lead in with Palbociclib (starting on 
Day -7) 
2. Only perform for females of child bearing potential (serum or urine) 
3. Blood to be drawn prior to administration of palbociclib and dexamethasone on day 
+1, and day +8. PK samples will be one tube of 3-4mL. PD samples are 10mL each.  
4. The bone marrow aspirate may be replaced by 20 mLs of peripheral blood if the 
patient has a peripheral leukemic blast count ≥200/l. 
5. In patients who attain a CR, a bone marrow should ONLY be performed after cycle 1 
maintenance if there is a suspicion/evidence of relapse based on peripheral blood 
studies or other clinical indications during the follow up period. 
6. All AEs will be followed until resolution. Patients will be monitored for AEs for 30 
daysafter the end of therapy or until initiation of a new anti-cancer therapy. 
7. Serum chemistry and electrolytes labs should include: creatinine, BUN, glucose, 
magnesium, phosphate, and urate. Liver function labs should include: bilirubin, SGOT 
(AST), SGPT (ALT), alkaline phosphatase.  
8. Patients will be followed for disease status until relapse/progression 
9. Correlative studies will be performed by the Calabretta laboratory on peripheral blood 
or bone marrow. 
10. Labs and bone marrow biopsy/aspirate may be performed ±2 days from the desired 
study day. 
11. Patients who remain on maintenance for >6 months may have labs checked monthly. 
 

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APPENDIX B: ECOG PERFORMANCE STATUS 
Grade  
ECOG 
0 
 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work 
2 
 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
  
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair 
5 
Dead 
As published in Am. J. Clin. Oncol.:Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C: SAMPLE HANDLING, PROCESSING, and STORAGE 
INSTRUCTIONS FOR PK and PD SAMPLES 
 

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Laboratory Address: PPD Inc 2244 Dabney Road 
Richmond, VA 23230-3323 United States 
Suggested Sampling, Handling, Processing, and Storage Information for PD Analyses 
Pre-treatment and post-treatment peripheral blood and/or bone marrow samples (10 mL/each) 
will be collected in heparinized 10-ml green-top tubes and transported in ice to Dr. Calabretta’s 
laboratory (Bluemle Building room 630).  Samples will be immediately processed by removing 
red blood cells using an Ammonium Chloride solution (Stem Cell Technology). Then, 
mononuclear cells will be purified through Ficoll Hypaque centrifugation and subjected to FACS-
sorting to isolate CD19+ B-cells. From these cells, we will obtain whole lysates for western blot 
analyses and total RNA for gene expression profiles (microarrays or RNA-Seq). Cell lysates and 
RNAs will be stored at -70 degrees. We anticipate that we will obtain enough cells (ideally, 5-10 
x 106 cells/sample) to extract proteins and RNA. If the number of CD19+ cells is insufficient, we 
will give priority to the preparation of whole cell lysates for western blot analyses of palbociclib 
and dexamethasone response biomarkers. 

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Appendix D: Requesting a Dose Escalation/Expansion Approval 
 
 
 
 

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Appendix E: Pfizer SAE Report Form 
 
 
 
 

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