A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma
Phase: PHASE2
Conditions: Glioblastoma
Sponsor: Dana-Farber Cancer Institute

 
 
 
1 
Ivy Foundation Early Phase Clinical Trials Consortium 
A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
 
 
Protocol Version No. / Date: 
4.0 / 13-July-2021 
 
DF/HCC Protocol No.: 
 
16-383 
 
Coordinating Center: 
 
 
 
Dana-Farber Cancer Institute 
 
Principal Investigator 
Eudocia Quant Lee, MD 
Dana-Farber/Brigham and Women’s 
Cancer Center 
Center for Neuro-Oncology 
450 Brookline Ave, DA2108A 
Boston, MA 02115-6084 
Phone: (617) 632-2166 
Fax: (617) 632-4773 
Email: eqlee@partners.org 
Biostatisticians 
Alona Muzikansky, MA 
Massachusetts General Hospital 
Biostatistics Center 
50 Staniford Street, Suite 560 
Boston, MA  02114 
Phone: 617-724-6985 
Fax: 617-724-9878 
Email: amuzikansky@partners.org  
Co-Investigator 
Jennie Taylor, MD 
University of California, San 
Francisco 
400 Parnassus Avenue, A808 
San Fransisco, CA 94143-0372 
Phone: (415) 353-2966 
Fax: (415) 353-2173 
Email: jennie.taylor@ucsf.edu 
 
Co-Investigator 
Isabel Arrillaga-Romany, MD, 
PhD 
Massachusetts General Hospital 
Department of Neurology 
Yawkey 9E 
55 Fruit Street 
Boston, MA 02114 
Phone: (617) 724-2887 
Fax: (617) 643-8769 
Email: iarrillaga@mgh.harvard.edu 
 
Co-Investigator 
Timothy Cloughesy, MD 
University of California Los 
Angeles 
Department of Neurology 
710 Westwood Plaza, Room 1-230 
Los Angeles, CA 90095 
Phone: (310) 825-5321 
Fax: (310) 825-0644 
Email: 
tcloughesy@mednet.ucla.edu 
Co-Investigator 
Thomas Kaley, MD 
Memorial Sloan-Kettering Cancer 
Center 
1275 York Ave., Mailbox 20 
New York, NY 10065 
Phone: (212) 610-0239 
Fax: (646) 227-2461 
Email: darasm@mskcc.org 
 
Co-Investigator 
John DeGroot, MD 
UT, M.D. Anderson Cancer Center 
Department of Neuro-Oncology, 
Unit 431 
1515 Holcombe Boulevard 
Houston, TX 77030 
Phone: (713) 745-3072 
Fax: (713) 794-4999 
Email: jdegroot@mdanderson.org 
Co-Investigator 
Howard Colman, MD, PhD 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Phone: (801) 587-4042 
Fax:  (801) 585-8613 
Email: 
howard.colman@hci.utah.edu 
Co-Investigator 
Mitch A. Phelps, PhD 
The Ohio State University 
College of Pharmacy and 
Comprehensive Cancer Center  
506 Riffe 
496 West 12th Avenue 
Columbus, Ohio 43210 
Phone: 614-688-4370 
Email: phelps.32@osu.edu 
 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
2 
Co-Investigator 
Keith Ligon, MD, PhD 
Center for Molecular Oncologic 
Pathology 
Dana-Farber/Brigham and Women’s 
Cancer Center 
450 Brookline Ave,  JFB 215B 
Boston, MA 02215-6084 
Phone: 617-632-2357 
Fax: 617-582-8761 
Email:  kligon@partners.org  
Co-Investigator 
Patrick Wen, MD 
Dana-Farber/Brigham and 
Women’s Cancer Center 
Center for Neuro-Oncology 
450 Brookline Ave, DA2108A 
Boston, MA 02115-6084 
Phone: (617) 632-2166 
Fax: (617) 632-4773 
Email: pwen@partners.org 
Co-Investigator 
Robert M. Prins, PhD 
UCLA Dept. of Neurosurgery 
Gonda Research Lab, Room 1554 
695 Charles E. Young Drive South 
Los Angeles, CA   
Phone: 310-794-5663 
Fax: N/A 
Email: RPrins@mednet.ucla.edu 
 
 
Co-Investigator 
J. Ricardo McFaline Figueroa, 
MD, PhD 
Dana-Farber/Brigham and Women’s 
Cancer Center 
Center for Neuro-Oncology 
450 Brookline Ave, DA2108A 
Boston, MA 02115-6084 
Phone: (617) 632-2166 
Fax: (617) 632-4773 
Email: 
jose_mcfalinefigueroa@dfci.harvard.
edu 
Co-Investigator 
Mario L. Suva, MD, PhD 
Massachusetts General Hospital  
MGH Partners Healthcare 
Molecular Pathology 
149 13th street, 7350, 7th, 149 
Charlestown, MA 02129 
Phone: 617 643 7533 
Fax: N/A 
Email: 
Suva.Mario@mgh.harvard.edu 
 
 
 
 
DFCI Coordinating Center:  
Kristen Fisher / Christine McCluskey / Jennifer Bruno 
 
Agent:  
Abemaciclib (LY2835219), supplied by Eli Lilly and 
Company 
 
IND #:  
131285 
 
IND Holder:   
Eudocia Quant Lee, MD, MPH  
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
3 
SCHEMA 
 
Cohort 1 will be treated concurrently with Cohort 2 
 
 
*The goal is to have 15 patients with adequate tissue for assessment of the primary objective.  If sufficient tissue is 
not obtained from a patient, an additional patient will be added to the cohort.  A maximum of 20 patients may be 
enrolled to this cohort. 
 
1 cycle = 4 weeks 
 
GBM= Glioblastoma 
CDKN2A/B = Cyclin Dependent Kinase 4 and 6 
RB = Retinoblastoma 
 
CR = complete response 
SD = stable disease 
 
PR = partial response   
PD = progressive disease 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
4 
TABLE OF CONTENTS 
SCHEMA 
 ...................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Study Design ......................................................................................................................9 
1.2 
Primary Objectives .............................................................................................................10 
1.3 
Secondary Objectives .........................................................................................................10 
1.4 
Exploratory Objectives ......................................................................................................10 
2. 
BACKGROUND ...............................................................................................................11 
2.1 
Glioblastoma ....................................................................................................................11 
2.2 
Abemaciclib (LY2835219) ................................................................................................12 
2.3 
Rationale For Phase II Trial of Abemaciclib in Recurrent Glioblastomas ........................14 
2.4 
Rationale For Phase 0 Study of Abemaciclib in Recurrent Glioblastomas .......................15 
2.5 
Correlative Studies Background ........................................................................................16 
3. 
PARTICIPANT SELECTION ...........................................................................................17 
3.1 
Eligibility Criteria ..............................................................................................................17 
3.2 
Exclusion Criteria ..............................................................................................................21 
3.3 
Inclusion of Women and Minorities ..................................................................................23 
4. 
REGISTRATION PROCEDURES ...................................................................................23 
4.1 
General Guidelines for DF/HCC Institutions ....................................................................23 
4.2 
Registration Process for DF/HCC Institutions ...................................................................23 
4.3 
General Guidelines for Other Investigative Sites ..............................................................24 
4.4 
Registration Process for Other Investigative Sites .............................................................24 
5. 
TREATMENT PLAN ........................................................................................................24 
5.1 
Treatment Regimen ............................................................................................................24 
5.2 
Cohort 1—Surgery Arm ....................................................................................................25 
5.3 
Cohort 2—Treatment Arm .................................................................................................26 
5.4 
General Concomitant Medication and Supportive Care Guidelines ..................................26 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .....................................................29 
5.6 
Duration of Follow Up .......................................................................................................29 
5.7 
Criteria for Taking a Participant Off Study .......................................................................30 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................30 
6.1 
Anticipated Toxicities ........................................................................................................32 
6.2 
Dose Modifications/Delays ................................................................................................33 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................40 
7.1 
General Information and Periods of Observation, Recording and Reporting ....................40 
7.2 
Expected Toxicities ............................................................................................................41 
7.3 
Adverse Event Characteristics ...........................................................................................41 
7.4 
Expedited Adverse Event Reporting ..................................................................................42 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) ..................................45 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
5 
7.6 
Expedited Reporting to Hospital Risk Management .........................................................45 
7.7 
Routine Adverse Event Reporting .....................................................................................45 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................45 
8.1 
Abemaciclib ....................................................................................................................45 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................48 
9.1 
Biomarker Studies from Any Prior Surgery ......................................................................48 
9.2 
Laboratory Correlative Studies ..........................................................................................48 
9.3 
Special Studies ...................................................................................................................62 
10. 
STUDY CALENDAR .......................................................................................................63 
11. 
MEASUREMENT OF EFFECT........................................................................................67 
11.1 
Antitumor Effect – Definitions ..........................................................................................67 
11.2 
Response/Progression Categories ......................................................................................68 
11.3 
Methods for Evaluation of Measurable Disease ................................................................70 
11.4 
Evaluation of Best Response .............................................................................................70 
11.5 
Other Effect Measures .......................................................................................................70 
11.6 
Response Review at DFCI Coordinating Center ...............................................................71 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................72 
12.1 
Data Reporting ...................................................................................................................72 
12.2 
Data Safety Monitoring ......................................................................................................72 
12.3 
Multicenter Guidelines .......................................................................................................73 
13. 
STATISTICAL CONSIDERATIONS...............................................................................73 
13.1 
Study Design ....................................................................................................................73 
13.2 
Endpoints 
....................................................................................................................74 
13.3 
Sample Size/Accrual Rate ..................................................................................................74 
13.4 
Analysis of Secondary and Exploratory Endpoints ...........................................................75 
13.5 
Reporting and Exclusions ..................................................................................................76 
14. 
DISCIPLINE REVIEW .....................................................................................................76 
14.1 
Central Pathology Review .................................................................................................76 
14.2 
Central Radiology Review .................................................................................................76 
15. 
PUBLICATION PLAN AND DISCLOSURE POLICY ...................................................76 
REFERENCES 
....................................................................................................................78 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..............................................80 
APPENDIX B 
MULTI-CENTER DSMP ........................................................................81 
APPENDIX C  
REPORTABLE AE COVERSHEET .....................................................99 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
6 
APPENDIX D 
INFORMATION ON POSSIBLE DRUG INTERACTIONS............100 
APPENDIX E 
ABEMACICLIB DOSING INSTRUCTIONS & DRUG DIARY 
(POST-SURGERY COHORT 1 & COHORT 2) ........................................................103 
APPENDIX F 
ABEMACICLIB DOSING INSTRUCTIONS & DRUG DIARY 
(COHORT 1 PRE-SURGERY) ....................................................................................106 
APPENDIX G 
MRI ACQUISITION PROTOCOL .....................................................108 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
7 
List of abbreviations  
 
AE  
Adverse Event 
ALT  
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC  
Absolute Neutrophil Count 
AST  
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
BUN  
Blood Urea Nitrogen 
CBC  
Complete Blood Count 
CDK 
Cyclin Dependent Kinase 
CK  
Creatine Kinase 
CK-MB  
Creatine Kinase - Muscle and Brain isoenzyme 
CR  
Complete Response 
CRD  
Clinical Research and Development 
CT  
Computed Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
DLT  
Dose Limiting Toxicity 
DSMB  
Drug Safety Monitoring Board 
ECG  
Electrocardiogram 
GBM 
Glioblastoma 
GCP  
Good Clinical Practice 
GI  
Gastrointestinal 
HIV  
Human Immunodeficiency Virus 
HDL  
High density lipoprotein 
ICH  
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IEC  
Independent Ethics Committee 
IRB  
Institutional Review Board 
LDL  
Low density lipoprotein 
LVEF  
Left Ventricular Ejection fraction 
MRI  
Magnetic Resonance Imaging 
MTD  
Maximum Tolerated Dose 
OS 
Overall Survival 
PD  
Pharmacodynamic 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PFS6 
6 Month Progression Free Survival 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
8 
PK  
Pharmacokinetic 
PR 
Partial Response 
PT  
Prothrombin Time 
PTT  
Partial Thromboplastin Time (also known as APTT) 
QTc  
QT interval (corrected) 
RANO 
Response Assessment in Neuro-Oncology 
RB 
Retinoblastoma 
RBC 
Red Blood Cells 
REB  
Research Ethics Board 
RECIST  
Response Evaluation in Solid Tumors 
SAE  
Serious Adverse Event 
SD 
Stable Disease 
SOP  
Standard Operating Procedure 
ULN  
Upper Limit of Normal 
WBC  
White Blood Count 
WCBP  
Women of Childbearing Potential 
WHO  
World Health Organization 
 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
9 
1. OBJECTIVES 
 
1.1 
Study Design 
 
This will be an open label, multi-center, phase 0/II trial of abemaciclib (LY2835219) in 
participants with recurrent glioblastoma (GBM) at their first or second relapse. Patients must 
have documented evidence of CDKN2A/B loss and intact RB in previously obtained tumor 
tissue by exome sequencing, copy number analysis [e.g. array comparative genomic 
hybridization (CGH)] and/or IHC for RB prior to enrollment into the study. 
 
In the phase 0 surgical arm (cohort 1), fifteen participants who require reoperation and have 
evidence of CDKN2A/B loss and intact RB from a prior tumor sample will receive a short 
preoperative course of abemaciclib for 10-14 days. Tissue will be used to investigate the ability 
of abemaciclib to pass through the blood brain barrier (BBB), achieve therapeutic concentrations 
in the tumor, and inhibit cellular proliferation in tumor tissue. Immunohistochemistry analysis 
for pRB, KI67, p21, and cleaved caspase 3 in tumor tissue obtained during the surgery as 
compared with tissue from a prior surgery will be used as a measure of decreased tumor cell 
proliferation and increased tumor cell death.  In addition, as exploratory aims, we will perform 
functional biomarker analysis on live cells and patient derived cell lines and xenografts obtained 
from cohort 1 patients in order to determine their response to abemaciclib and investigate the 
associations between clinical outcomes and immunologic effects of abemaciclib. After surgery, 
cohort 1 participants will come off study treatment and pursue standard cancer treatments as per 
the treating physician’s discretion. 
 
The phase II treatment arm (cohort 2) will be comprised of 32 participants not requiring surgery.  
Participants will receive treatment with abemaciclib for each 28 day cycle (if participant tolerates 
first cycle of treatment well, abemaciclib may be increased for all subsequent cycles if the 
investigator determines that it is in the best interest of the patient).  The primary endpoint is to 
determine the overall efficacy of abemaciclib as determined by six-month progression free 
survival (PFS6). Participants will remain on treatment until tumor progression, as long as there 
are no unacceptable toxicities. Responses will be assessed by clinical examinations every 4 
weeks and MRI scans every 8 weeks. Responses determined using the new Response 
Assessment in Neuro-Oncology (RANO) criteria (Wen et al., 2010). 
 
Limited pharmacokinetic studies will be performed to ensure that there is no significant 
difference in patients with GBM compared to other solid tumors. Because the extent to which 
abemaciclib is metabolized by cytochrome P450 enzymes such as 3A4, is unknown, the 
concurrent use of enzyme-inducing anti-epileptic drugs (EIAEDs) such as phenobarbital, 
phenytoin, carbamazepine, and oxcarbazepine will not be permitted as these drugs may result in 
reduced exposure to abemaciclib. Since the vast majority of glioblastoma patients are no longer 
taking EIAEDs, this will not significantly affect patient accrual.   
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
10 
1.2 
Primary Objectives 
 
1.2.1 Cohort 1 
• 
To evaluate abemaciclib concentration in tumor tissue. 
 
1.2.2 Cohort 2 
• 
To investigate the treatment efficacy of abemaciclib in participants with recurrent 
GBM as measured by 6-month progressive-free survival (PFS6). 
 
1.3 
Secondary Objectives 
 
1.3.1 Cohort 1 
• 
To evaluate effects of abemaciclib on phospho-RB (S807/811), tumor cell 
proliferation (Ki67) and tumor cell death (CC3, p21) by immunohistochemistry 
(IHC). 
• 
To investigate pharmacokinetics of abemaciclib in participants with recurrent 
GBM. 
• 
To investigate the safety profile of abemaciclib in participants with recurrent 
GBM. 
 
1.3.2 Cohort 2 
• 
To investigate the radiographic response (RR) to abemaciclib. 
• 
To investigate median progression free survival (PFS) and overall survival (OS) 
of participants with recurrent GBM receiving treatment with abemaciclib. 
• 
To investigate pharmacokinetics of abemaciclib in participants with recurrent 
GBM. 
• 
To investigate the safety profile of abemaciclib in participants with recurrent 
GBM. 
 
1.4 
Exploratory Objectives 
 
1.4.1 Cohort 1 
• 
To investigate associations between clinical outcomes and immunologic effects of 
abemaciclib including quantitative assessments of tumor infiltrating lymphocytes 
(TIL) that express PD-1, delineation of PD-L1+ cells in the tumor 
microenvironment, assessment of immune pathways pretreatment and 
posttreatment, and quantitative assessment of T cell receptors from tumor samples 
pretreatment and posttreatment.  
• 
To investigate the effects of abemaciclib on cellular programs as characterized 
using single-cell RNA-sequencing based on tumor samples posttreatment in 
comparison to historical untreated controls. 
• 
To investigate the effects of abemaciclib on tumoral antigen presentation and the 
immune milieu of the tumor microenvironment based on tumor samples 
posttreatment in comparison to historical untreated controls. 
• 
To investigate the effects of abemaciclib on patient-derived cells (PDC), cell lines 
(PDCL) and xenografts (PDX) established from patients on the study. 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
11 
 
1.4.2 Cohort 2 
• 
To correlate response to treatment with molecular phenotype of pre-treatment 
tumor (Oncopanel sequencing and array CGH copy number analysis);  
• 
To investigate the mechanisms of resistance to abemaciclib by examining tumor 
tissue obtained from patients who progress on treatment, when available, with 
pretreatment tumor. 
 
 
2. BACKGROUND 
 
2.1 
Glioblastoma 
 
Glioblastomas are the most common type of malignant primary brain tumors in adults and 
accounts for 15.4% of all primary brain tumors (Ostrom et al., 2014). The annual incidence rate 
of GBM in the United States is 3.19 per 100,000. Despite optimal treatment with surgery, 
radiation therapy, and chemotherapy, the prognosis remains poor. In 2005, results from a 
randomized phase III trial indicated that the addition of temozolomide chemotherapy to radiation 
therapy for treatment of newly-diagnosed GBM prolonged median overall survival (OS) from 
12.1 to 14.6 months (Stupp et al., 2005). For patients with glioblastomas whose tumors recur, the 
median time to tumor progression is only 9 weeks and median survival is 25 weeks (Wong et al., 
1999). Once patients develop tumor progression, conventional chemotherapy is generally 
ineffective. Several reasons account for this poor response to chemotherapy including reduced 
drug delivery as a result of the blood-brain barrier, intrinsic resistance to many cytotoxic agents, 
tumor hypoxia, and a relatively low growth fraction. There is a need for more effective therapies 
based on novel mechanisms of action (Wen & Kesari, 2008).  
 
Role of the CDK4/6 –RB Pathway in the Molecular Pathogenesis of Glioblastomas 
 
Deregulation of the cyclin-dependent kinases (CDK) 4 and 6 (cdk4/6)–cyclin D-INK4—
retinoblastoma protein (Rb) signaling pathway is among the most common aberrations found in 
glioblastomas with more than 80% of patients estimated to be affected (Brennan et al., 2013). 
This pathway is most commonly altered by homozygous deletion of CDKN2A/B, and less 
commonly by deletion/mutation of CDKN2C and RB1, or genomic amplification of CDK4, 
CDK6, and individual D-type cyclins (Brennan et al., 2013; Dunn et al., 2012; Wiedemeyer et 
al., 2008). Recent molecular profiling of GBM has further highlighted the critical role of 
CDK4/6 activation in the pathogenesis of this devastating tumor (Brennan et al., 2013). In 
preclinical studies with the CDK4/6 inhibitor palbociclib (PD-0332991) in GBM cell lines and 
orthotopic models, there was potent induction of G1 cell cycle arrest, and induction of 
senescence in each of 16 retinoblastoma protein (Rb)–proficient cell lines regardless of other 
genetic lesions, whereas 5 cell lines with homozygous inactivation of Rb were completely 
resistant to treatment, suggesting that Rb status is the primary determinant of potential benefit 
from this therapy (Michaud et al., 2010). The combination of palbociclib and radiation therapy 
resulted in significantly increased survival benefit compared with either therapy alone (Michaud 
et al., 2010). Another study produced somewhat similar findings with GBM lacking CDKN2A/B 
expression and with non-amplified CDK4 and wild-type RB status showing more susceptibility 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
12 
to Cdk4/6 inhibition using palbociclib (PD0332991) (Cen et al., 2012). 
 
2.2 
Abemaciclib (LY2835219) 
 
Abemaciclib (LY2835219) is a selective and potent small molecule CDK4/6 dual inhibitor that is 
hypothesized to arrest tumor growth through prevention of cell cycle progression through the G1 
restriction point. In humans, one study has been completed (I3Y-MC-JPBD [JPBD]) and 13 
studies are ongoing including I3Y-MC-JPBA, I3Y-MC-JPBB, I3Y-JE- JPBC, I3Y-MC-JPBE, 
I3Y-MC-JPBH, I3Y-MC-JPBJ, and I3Y-MC-JPBN. 
 
Absorption, Distribution, Metabolism, and Excretion 
 
Abemaciclib (LY2835219) demonstrates moderate to high bioavailability in preclinical species. 
In humans, the terminal elimination half-life (t1/2) in plasma ranges from approximately 17 to 38 
hours across the dose range tested. At a single dose of 200 mg, the mean apparent oral clearance 
is 38.3 L/h with high inter-individual variability (105% coefficient of variation [CV]) and the 
apparent volume of distribution is large at 1300 L (96% CV). Following oral administration, 
abemaciclib was extensively metabolized followed by biliary excretion of metabolites. 
 
Based on Study JPBD and in vitro data, CYP3A is responsible for abemaciclib metabolism, the 
primary route of clearance. Strong CYP3A inhibitors may increase abemaciclib exposures, and 
strong inducers may decrease abemaciclib exposures. Abemaciclib and its major metabolites did 
not substantially inhibit CYP enzymes in human liver microsomes; however, there was 
downregulation of mRNA for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A. 
Caution should be exercised when coadministering abemaciclib with narrow therapeutic drugs 
that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, or CYP3A. 
 
The abemaciclib (LY2835219) radioactivity associated with [14C] abemaciclib (LY2835219) 
distributes well into tissues and organs, with radioactivity concentrations measurable through 24 
hours post-dose in various parts of brain in rat.  Abemaciclib (LY2835219) therefore distributes 
extensively to the brain in vivo and produces a statistically significant and dose dependent 
improvement in survival in a rat orthotopic brain tumor model.  Median survival was improved 8 
and 12 days compared to vehicle following daily oral treatment at 40 mg/kg and 80 mg/kg for 21 
days, respectively.  Preclinical data demonstrates that abemaciclib (LY2835219 mesylate inhibits 
CDK4/6 to induce G1 arrest specifically in Rb-proficient tumors. In primary human tumor 
xenograft models, abemaciclib (LY2835219) also demonstrates tumor growth delay and a 
prolongation of survival.  Abemaciclib (LY2835219) was initiated day 6 post tumor cell 
injection as oral gavage once daily at either 45 or 90 mg/kg/administration. Normalized 
bioluminescence was reduced in tumors treated with either dose level, which led to a statistically 
significant improvement in survival. In GBM human xenograft models, growth inhibition was 
generally dose dependent from 25 to 100 mg/kg following daily oral administration for 21 days. 
 
In another study orally dosed abemaciclib significantly increased survival in a rat orthotopic 
U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a 
dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and 
CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
13 
similar to temozolomide (TMZ), and the combination of abemaciclib and TMZ was additive or 
greater than additive. These data show that abemaciclib crosses the blood–brain barrier and 
confirm that both abemaciclib and another CDK4 and CDK6 inhibitor, palbociclib, reached 
unbound brain levels in rodents that are expected to produce enzyme inhibition; however, 
abemaciclib brain levels were reached more efficiently at presumably lower doses than 
palbociclib and were potentially on target for a longer period of time.(Raub et al., 2015). 
 
 
In other preclinical data we studied effects of abemaciclib 
(LY2835219) on a panel of GBM patient derived cell line 
models (PDCLs) which faithfully recapitulate the biology 
and genotype of GBM patients along with their diversity. 
This work shows that the initial biomarker hypothesis 
that CDKN2A homozygous deletion (or greater than 1 
copy loss) is associated with increased sensitivity to the 
drug and CDK4 amplification is associated with relative 
resistance. 
 
Cerebrospinal fluid (CSF) samples were collected from a 
limited number of patients with brain metastases in Study 
JPBA on Day 15 of Cycle 1 after repeated Q12H dosing. 
In general, abemaciclib concentrations in CSF were 
consistent with unbound plasma concentrations. The 
metabolite concentrations were lower than abemaciclib 
concentrations and in some patients below the lower limit 
of quantitation (1 ng/mL). 
 
Dosing and Method of Administration 
 
Abemaciclib has been administered orally on Days 1 through 28 of a 28-day cycle. In Study 
JPBA, the MTD for humans when administered as a single agent is 200 mg Q12H. During the 
tumor-specific expansion phases of JPBA, patients initially received abemaciclib at the MTD of 
200 mg Q12 hours. A preliminary interim safety review with data from 56 patients indicated that 
29 patients experienced diarrhea possibly related to study drug: 17 Grade 1 (30%), 9 Grade 2 
(16%), 3 Grade 3 (5%), none Grade 4 (0%), and none Grade 5 (0%). Based on the frequency of 
Grade 1/2 diarrhea and the observation of clinical activity at doses below the MTD, the initial 
starting dose was changed to 150 mg every 12 hours to gain additional PK data and clinical 
experience around safety/tolerability. Based on this further clinical experience (demonstrating 
that the diarrhea experienced by patients is manageable with standard anti-diarrheal agents such 
as loperamide) the study was further amended to again allow starting doses of 200 mg Q12H. 
Therefore, for safety, the starting dose of abemaciclib in this phase 2 study in recurrent GBM 
will be 150 mg Q12H. Abemaciclib may be escalated at the start of Cycle 2 to 200 mg Q12H if 
the investigator determines that it is in the best interest of the patient.   
 
Dosages for pediatric and geriatric populations are not known at this time. There is no 
information for dosage adjustments in patients with renal insufficiency, hepatic insufficiency, or 
 
 
Figure 1. GBM PDCLs treated with LY2835219 
(Abemaciclib) show differential response based on 
genotype with CDKN2A deleted  lines (>1 copy 
loss) being more sensitive than lines with intact 
CDKN2A.. (Ligon and Wen, unpublished)  
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
14 
concomitant disease, or who are undergoing dialysis.  
 
Safety and Efficacy 
 
Validated safety data for 352 patients treated with abemaciclib in Studies JPBA, JPBB, JPBC, 
JPBH, JPBJ, and JPBN are available. Cumulatively, the most common TEAEs (≥10%) possibly 
related to study drug for patients receiving abemaciclib either as a single agent, with endocrine 
therapy, or with chemotherapy, are diarrhea (64.2%), nausea (44.3%), fatigue (39.8%), 
neutropenia (27.0%), vomiting (24.1%), thrombocytopenia (21.3%), leukopenia (21.0%), anemia 
(17.6%), decreased appetite (17.6%), and blood creatinine increased (14.5%).  
 
The majority of deaths reported for patients in the studies with available safety data were due to 
study disease. 
 
As of 14 October 2014, 31 patients in Studies JPBA, JPBB, JPBC, JPBE, JPBH, JPBJ, and JPBN 
experienced 43 SAEs that were reported as possibly related to study drug. SAEs that were 
possibly related to study drug and experienced by more than 1 patient included diarrhea (5 
patients), dehydration (4 patients), neutropenia and pneumonia (3 patients each), and anemia, 
confusional state, nausea, pyrexia, and sepsis (2 patients each). 
 
Study JPBA was a phase 1 study of abemaciclib in patients with advanced cancer and included 
some patients with primary brain tumors or brain metastases. Plasma and CSF concentrations of 
abemaciclib were obtained in patients with primary brain tumors or brain metastases after 
reaching steady state with < 2.5 hours between plasma and CSF sampling. The results supported 
the preclinical observations of distribution extensively in the CSF. Seventeen patients with GBM 
that had progressed or recurred after radiotherapy and/or chemotherapy enrolled in the tumor-
specific expansion phase (Part C) of study JPBA.  Abemaciclib was given as a single agent at a 
dose of 200 mg orally every 12 hours on Days 1 through 28 of a 28-day cycle.  In this 
progressive/recurrent GBM cohort of unselected patients, the disease control rate (DCR = 
response + stable disease) was 17.6% and median PFS was 1.1 months.  It should be noted that 
13 of the 17 patients were heavily pretreated patients who had failed bevacizumab. In the 4 
heavily pretreated patients who had not received bevacizumab, 2 patients experienced prolonged 
disease stability (1 patient had received 19 cycles and 1 patient had received 24 cycles at data 
cutoff). Both remained on treatment with stable disease at data cutoff. 
 
Clinical Pharmacodynamics 
 
In the colorectal (Colo-205) xenograft model and skin biopsies from patients in Study I3Y-MC-
JPBA (JPBA), abemaciclib inhibited phosphorylated Rb [pRb], and topoisomerase II alpha 
[TopoIIα] at clinically relevant doses and exposures. 
 
2.3 
Rationale For Phase II Trial of Abemaciclib in Recurrent Glioblastomas 
 
Deregulation of the cdk4/6–cyclin D-INK4—Rb signaling pathway is among the most common 
genomic aberrations found in GBM (78% of patients) and plays an important role in its 
pathogenesis (TCGA 2008; Brennan, Verhaak et al. 2013). In vitro and in vivo studies with 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
15 
cdk4/6 inhibitors demonstrate potent induction of G1 cell cycle arrest and antitumor activity 
(Cen et al., 2012; Michaud et al., 2010; Raub et al., 2015). Studies also suggest that Rb status is 
the primary determinant of potential benefit from this therapy (Michaud, Solomon et al. 2010). 
Abemaciclib (LY2835219) is a selective and potent small molecule CDK4/6 dual inhibitor that 
distributes extensively in brain. In human GBM xenograft models, abemaciclib demonstrated 
tumor growth delay. For these reasons, we propose a phase II study of abemaciclib in 
participants with recurrent glioblastoma with loss of CDKN2A/B and intact RB to evaluate its 
antitumor activity (Cohort 2).  
 
2.4 
Rationale For Phase 0 Study of Abemaciclib in Recurrent Glioblastomas 
 
We will examine a PK/PD cohort of 15 participants (Cohort 1) where abemaciclib will be 
administered for 10-14 days prior to surgery and treated tumor specimens will be examined for 
drug concentrations and evidence of inhibition of cellular proliferation (KI67) cell death (CC3 
and p21) and decreased phospho-Rb (pRb) in tumor tissue to confirm the ability of abemaciclib 
to pass through the blood-brain barrier and produce a pharmacodynamic effect in vivo. 
 
Data from Jean Zhao and colleagues also suggest that CDK4/6 inhibitors increase tumor 
immunogenicity (Goel et al., 2017). Based on murine models of solid tumors including GBM, 
selective CDK4/6 inhibitors not only induce tumor cell cycle arrest, but also promote anti-tumor 
immunity via two distinct elements: first, CDK4/6 inhibitors activate tumor cell expression of 
endogenous retroviral elements, thus increasing intracellular double-stranded RNA levels. This 
in turn stimulates production of type III interferons and thence increases tumor antigen 
presentation; second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells 
(Tregs). Mechanistically, each of these phenomena is associated with reduced activity of DNA 
methyltransferase 1 (in tumor cells and Tregs respectively), the expression of which is controlled 
by the CDK4/6-RB-E2F pathway. Ultimately, this leads to cytotoxic T cell-mediated clearance 
of tumor cells, which is further enhanced by the addition of immune checkpoint blockade. In the 
same PK/PD cohort of 15 participants (Cohort 1) where abemaciclib will be administered prior 
to surgery, treated tumor specimens will be examined for immunologic biomarkers such as the 
density of T lymphocytes within tumor tissue and the T cell receptor (TCR) clonality.  
 
As the study continued, the nonsurgical cohort (Cohort 2) completed accrual while the surgical 
cohort (Cohort 1) remained open. Outcomes data were reviewed in the nonsurgical cohort 
(Cohort 2) demonstrating limited benefit from abemaciclib monotherapy with a PFS6 rate of 
9.37% [95% CI, 2.4%, 22.27%], median PFS 55 days [95% CI, 49, 56], and median OS 384 days 
[95% CI, 228, 488]. Nonetheless, a surgical cohort still provides valuable information to 
understanding why abemaciclib has limited activity in recurrent GBM patients and whether it 
helps enhance the antitumor immune response (Goel et al., 2017). Therefore, the study was 
amended further to convert the remaining slots in the surgical cohort (Cohort 1) into a Phase 0 
study. The study design remains the same (pretreatment with abemaciclib followed by surgery 
with correlative studies) except that participants will come off study treatment after surgery and 
pursue standard cancer treatments as per the treating physician’s discretion. The purpose of this 
phase 0 study is not to treat the tumor but to determine tumor tissue PK and PD. This phase 0 
study does not replace routine cancer treatment. 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
16 
 
 
2.5 
Correlative Studies Background 
 
Cohort 1: In this cohort, patients with recurrent GBM will receive drug for 10-14 days prior to a 
reoperation. Tumor will be resected and analyzed for: 
 
1) Pre-treatment tumor will be genotyped with next generation sequencing and the results 
correlated with outcome if not previously performed.  
2) Drug concentration using liquid chromatography - tandem mass spectrometry (LC-
MS/MS). Tumor concentration will be compared to plasma drug concentrations to 
determine if therapeutic levels of abemaciclib can be achieved in both enhancing and 
non-enhancing tumor. 
3) Tumor tissue will be analyzed by IHC and proteomics analysis for Phospho-Rb, 
(S807/811) proliferation (Ki-67), and apoptosis (cleaved caspase 3) to determine if 
abemaciclib can achieve a pharmacodynamic effect in enhancing and non-enhancing 
tumor tissue. These data will be compared to results from the patient’s prior archived 
tumor tissue not exposed to abemaciclib obtained from each participant’s prior surgery, 
and to results from unrelated glioblastoma patients (n=10) with tumor tissue from pre- 
and post-treatment with standard of care RT+TMZ. 
4) Tumor tissue will be analyzed for quantitative assessment of TIL that express PD-1, 
delineation of PD-L1+ cells in the tumor microenvironment (macrophage vs. tumor 
cells), immune response based multiplex gene expression analysis in tumor samples pre- 
and post-treatment, and quantitative assessment of T cell receptors in tumor samples pre- 
and post-treatment 
5) Tumor tissue will be analyzed for tumoral expression of major histocompatibility 
complex type I and II, markers of T-cell exhaustion, type III interferon production and 
profiling of the immune milieu of the tumor microenvironment by multiplexed 
immunofluorescence (IF), and activation of abemaciclib-induced intrinsic anti-tumor 
immunity by gene expression analysis. 
6) If sufficient tumor is available, fresh patient derived cells (PDC), patient-derived cell 
lines (PDCL), and patient derived xenografts (PDX) will be attempted to be generated.  
7) Fresh cells or PDCL/PDX models will undergo functional sensitivity testing to 
abemaciclib or studied using genomics or expression analysis. 
 
Cohort 2: Tumor from the participant’s surgery prior to enrolling onto the study will be studied 
for correlative markers. 
 
1) Pre-treatment tumor will be genotyped with next generation sequencing and the results 
correlated with outcome if not previously performed.  
2) IHC analysis of pRB, Ki67, and CC3 will be performed for correlation with outcome. 
3) Analysis of any cell lines derived from prior surgery will be studied if available. 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
17 
 
3. PARTICIPANT SELECTION 
 
Screening evaluations are detailed in Study Calendar (Section 10).  All assessments are to occur 
within 14 days of registration except where otherwise noted.  The participant must be thoroughly 
informed of all aspects of the study, including the study visit schedule and required evaluations 
and all regulatory requirements for informed consent.  The written informed consent must be 
obtained from the participant prior to enrollment.  
 
Following registration, any additional laboratory assessments obtained prior to start of treatment 
will not be used to re-confirm eligibility.  Please refer to Section 6.2 and Table 6.3 Dosing 
Delays/Dose Modifications for toxicity management between registration and start of study 
treatment.   
 
3.1 
Eligibility Criteria  
 
All participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
1. Participants must be able to understand and willing to sign a written informed consent 
document.  
2. Participants must be able to adhere to the dosing and visit schedules and agree to record 
medication times accurately and consistently in a daily diary. 
3. Participants must be at least 18 years old on day of signing informed consent.  
4. Participants must have a Karnofsky Performance Status (KPS) ≥ 60 (see Appendix A). 
5. Participants must be able to swallow tablets. 
6.  Participants with a prior or concurrent malignancy whose natural history or treatment 
does not have the potential to interfere with the safety or efficacy of the trial are eligible.  
NOTE: consultation with the Overall PI is highly recommended if enrollment of a 
participant with a prior or concurrent malignancy is being pursued.  
Nature of illness and treatment history 
7. Participants must undergo central pathology review to histologically confirm the 
diagnosis of glioblastoma, IDH-wildtype; glioblastoma variants; or astrocytoma, IDH-
mutant, WHO grade 4 (1 unstained slide or 1 H&E slide must be submitted to and 
reviewed by a pathologist at the DFCI Coordinating Center prior to enrollment of the 
participant for central pathology review).   
8. To be eligible for the study all participants (Cohort 1 and 2) are required to provide 
genomic profiling data from assays performed in a CLIA-certified lab. A sequencing-
based assay is required and must include reporting of the RB1 gene in explicit terms 
within the report. Only sequencing assays that include coverage of all exons of the RB1 
gene are able to be utilized (most commonly called a targeted exome assay; e.g. 
Oncopanel, Impact, FoundationOne). In addition, patients must provide a report of copy 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
18 
assessment which reports status of RB1. The reporting may be from a copy array (ideally 
Oncoscan SNP array or Agilent array CGH) or can also be from sequencing assay if copy 
status is explicitly provided with quantitative information regarding the status of relevant 
genes. Specifically, the reporting should provide the following information with respect 
to relevant biomarkers required for enrollment to the study as listed below.  
Results from genomic profiling must be sent to the DFCI Coordinating Center prior to 
enrollment of the participant for central pathology review. Central pathology can provide 
feedback on reports if requested to help in assessing status as needed. 
o Inactivation of CDKN2A/B or C in the tumor by homozygous deletion (evidence 
for more than single copy loss for any of the genes defined as array CGH/SNP 
log2 ratio of <0.3 by array CGH; or from sequencing data with sufficient 
coverage for evaluation). Rearrangement/evidence or intragenic breaks by copy or 
sequencing assay also will be considered eligible for study (any copy status). 
OR 
o CDK4 or CDK6 high-level amplification. (The amplicon size must be <10Mb and 
the magnitude the gain must be log2 ratio >1.5 or estimated as >10 copies). 
AND  
o Validation of wild-type RB status (no deletion/losses more than single copy by 
copy number or sequencing data; and/or no inactivating mutations or 
rearrangements by sequencing). 
9. Participants must be at first or second relapse of GBM.  Relapse is defined as progression 
following therapy.  The intent is that patients had no more than 2 prior therapies.  
10. Participants must have shown unequivocal evidence for tumor progression by MRI or CT 
scan.  
o For Cohort 2 subjects, CT or MRI within 14 days prior to study registration. For 
Cohort 2, corticosteroid dose must be stable or decreasing for at least 5 days prior 
to the scan. If steroids are added or the steroid dose is increased between the date 
of the screening MRI or CT scan and the start of treatment, a new baseline MRI 
or CT is required.  
o For Cohort 1 subjects, CT or MRI should be performed ideally within 14 days 
prior to study registration, but because the screening MRI for this subset of 
subjects will not be used for evaluation of response, it is acceptable for this 
MRI/CT to have been performed greater than 14 days prior to registration if 
unavoidable.  Furthermore, for this same reason, fluctuation in corticosteroid dose 
around this MRI does not warrant repeat scan so long as there is documented 
unequivocal evidence of tumor progression available. 
o For Cohort 1 subjects, there must be > 2cm2 enhancing tissue available for 
resection and submission for study correlatives as determined by local treating 
team.  
11. Confirmation of availability of sufficient tissue from a prior surgery for correlative 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
19 
studies is required prior to enrollment; these samples must be sent to the DFCI 
Coordinating Center within 60 days of registration. Cohort 1 participants must have 
sufficient FFPE tissue from any surgery. Cohort 2 participants must have tissue from 
biopsy or resection from the most recent recurrence surgery.  
The following amount of archived tissue is required: 
o 20 unstained formalin fixed paraffin embedded (FFPE) sections (standard 5 
micrometer thickness)  
NOTE: if the above-mentioned tissue is not available from the most recent surgery 
revealing GBM, participants may be enrolled with tissue available from any prior 
surgery revealing GBM with prospective approval from the Overall PI.  
12. An interval of at least 12 weeks from the completion of radiation therapy to start of study 
drug unless there is a new area of enhancement consistent with recurrent tumor outside 
the radiation field (defined as the region outside the high-dose region or 80% isodose 
line) or there is unequivocal histologic confirmation of tumor progression. If recurrence 
is outside the radiation field or there is histologic confirmation of tumor progression, then 
an interval of at least 14 days must have elapsed from completion of radiation therapy to 
start of study drug and participants must have fully recovered from the acute effects of 
radiotherapy.  
13. Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically 
significant toxic effects of prior therapy (including but not limited to exceptions of 
alopecia, laboratory values listed per inclusion criteria, and lymphopenia which is 
common after therapy with temozolomide).  
14. From the projected start of scheduled study treatment, the following time periods must 
have elapsed:  
o 4 weeks or 5 half-lives (whichever is shorter) from any investigational agent; 
o 4 weeks from cytotoxic therapy (except 23 days for temozolomide; 6 weeks from 
nitrosoureas); 
o 4 weeks from antibodies; 
o 4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies. 
o 2 days from Novo-TTF 
15. Participants with prior therapy that included interstitial brachytherapy or stereotactic 
radiosurgery must have confirmation of progressive disease based upon nuclear imaging, 
MR spectroscopy, perfusion imaging or histopathology. 
16. Participants having undergone recent resection or open biopsy or stereotactic biopsy of 
recurrent or progressive tumor will be eligible for Cohort 2 as long as the following 
conditions apply: 
o They have recovered from the effects of surgery. 
o Residual disease following resection of recurrent tumor is not mandated for 
eligibility. To best assess the extent of residual disease post-operatively, an MRI 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
20 
or CT scan should ideally have been performed no later than 96 hours following 
surgery, or at least 28 days post-operatively, but scans performed outside of this 
window are considered acceptable if no alternative is available. In either case, the 
baseline/screening MRI must be performed within 14 days prior to registration. If 
the participant is taking corticosteroids, the dose must be stable or decreasing for 
at least 5 days prior to the scan.  If steroids are added or the steroid dose is 
increased between the date of the screening MRI or CT scan and the start of 
treatment, a new baseline MRI or CT is required.    
Clinical labs – performed within 14 days prior to registration 
17. Hematology: 
o Absolute neutrophil count (ANC) ≥ 1.5 x K/µL 
o Platelet count ≥ 100 x K/µL 
o Hemoglobin ≥ 8.0 g/dL 
18. Biochemistry: 
o Total serum calcium (corrected for serum albumin as needed) or ionized calcium 
within institution’s normal range. 
o Magnesium within institution’s normal range. 
o AST (SGOT) and ALT (SGPT) ≤ 3.0 x institution’s ULN 
o Serum bilirubin ≤ 1.5 x institution’s ULN. Patients with Gilbert’s syndrome with 
a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are 
permitted. 
o Serum creatinine ≤ 1.5 x institution’s ULN or calculated 24-hour creatinine 
clearance ≥ 50 mL/min 
o Serum amylase ≤ 1.5 x institution’s ULN  
o Serum lipase ≤ 1.5 x institution’s ULN 
19. Coagulation studies: 
o INR < 2.0  
o PTT ≤ institution’s ULN, unless receiving therapeutic low molecular weight 
heparin or oral factor Xa inhibitors.  
Pregnancy and Reproduction 
20. Based on findings in animals, abemaciclib can cause fetal harm when administered to a 
pregnant woman.  For this reason, women of child-bearing potential (WOCBP) must 
agree to use a highly effective contraceptive method during the treatment period and 
for 3 weeks following the last dose of abemaciclib.  Men must agree to use a reliable 
method of birth control and to not donate sperm during the study and for at least 3 weeks 
following the last dose of abemaciclib.  Contraceptive methods may include an 
intrauterine device [IUD] or barrier method.  If condoms are used as a barrier method, a 
spermicidal agent should be added as a double barrier protection.   
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
21 
o NOTE: Women are considered post-menopausal and not of child bearing potential 
if they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) 
or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL 
and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or 
without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential. 
21. Women of child-bearing potential must have a negative serum pregnancy test within 7 
days prior to first dose of abemaciclib.  
3.2 
Exclusion Criteria 
 
Participants who meet any of the following criteria will not be eligible for admission into the 
study. 
Pathology 
1. Prior evidence of 1p/19q co-deletion. 
Previous therapies 
2. Participants who have received prior treatment with a CDK4/6 inhibitor. 
3. Participants who have received anti-VEGF targeted agents (e.g. bevacizumab, cediranib, 
aflibercept, vandetanib, XL184, sunitinib etc). 
Concomitant medications 
4. Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital, 
phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, 
rufinamide, and felbamate. Participants must be off any EIAEDs for at least 14 days prior 
to starting study drug.  A list of EIAEDs and other inducers of CYP3A4 can be found in 
Appendix D. 
5. Participants taking a drug known to be a strong inhibitor or inducer of isoenzyme CYP3A 
(Appendix D). Participant must be off CYP3A inhibitors and inducers for at least 14 days 
prior to starting study drug. NOTE: participants must avoid consumption of Seville 
oranges (and juice), grapefruits or grapefruit juice, grapefruit hybrids, pummelos and 
exotic citrus fruits from 7 days prior to the first dose of study drug and during the entire 
study treatment period due to potential CYP3A4 interaction. 
6. Participants receiving any other investigational agents. 
7. Current use of herbal preparations/medications, including but not limited to: St. John’s 
wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, ginseng. Participants should stop using these herbal medications 
7 days prior to first dose of study drug. 
8. Current use of warfarin sodium or any other coumadin-derivative anticoagulant. 
Participants must be off Coumadin-derivative anticoagulants for at least 7 days prior to 
starting study drug. Low molecular weight heparin is allowed.  
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IRB NUMBER: 16-383
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A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
22 
9. Requires treatment with high dose systemic corticosteroids defined as dexamethasone > 4 
mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of registration.  
Other illnesses 
10. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to abemaciclib. 
11. History of intratumoral or peritumoral hemorrhage if deemed significant by the treating 
investigator.  If there are questions, the treating investigator should contact the study 
Overall P.I., Eudocia Quant Lee, MD, at 617-632-2166 or eqlee@partners.org. 
12. Serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the 
investigator, would preclude participation in this study including, but not limited to 
interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal 
impairment (e.g. estimated creatinine clearance <30ml/min), history of major surgical 
resection involving the stomach or small bowel,  preexisting Crohn’s disease or 
ulcerative colitis, chronic liver disease (e.g., cirrhosis, hepatitis), pancreatitis, chronic 
pulmonary disease, or psychiatric illness/social situations that would limit compliance 
with study requirements. Subjects must be free of any clinically relevant disease (other 
than glioma) that would, in the treating investigator’s opinion, interfere with the conduct 
of the study or study evaluations. 
13. Participant has an active systemic bacterial (requiring intravenous antibiotics at time of 
initiating study treatment), fungal infection, and/or detectable viral infection (for 
example, human immunodeficiency virus positivity, known active hepatitis B [for 
example, hepatitis surface antigen positive], or known active hepatitis C). Screening is 
not required for enrollment. 
14. Participants with diarrhea ≥ CTCAE grade 2 
15. Participant has active cardiac disease including any of the following: 
a. Angina pectoris that requires the use of anti-anginal medications 
b. Supraventricular and nodal arrythmias requiring a pacemaker or not controlled 
with medication 
c. Conduction abnormality requiring a pacemaker 
d. Valvular disease with document compromise in cardiac function  
e. Symptomatic pericarditis 
16. Participant has a history of cardiac dysfunction including any of the following: 
o Myocardial infarction within the last 6 months prior to start of study drug, 
documents by persistent elevated cardiac enzymes or persistent regional wall 
abnormalities on assessment of LVEF function 
o History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
o Active cardiomyopathy 
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IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
23 
o Congenital long QT syndrome 
o History of syncope of cardiovascular etiology 
o History of sudden cardiac arrest 
o History of ventricular arrhythmias of pathological origin including, but limited to, 
ventricular tachycardia and ventricular fibrillation   
17. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of abemaciclib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or extensive small bowel resection). Participants with 
unresolved diarrhea ≥ CTCAE grade 2 will be excluded as previously indicated. 
18. Participants who have undergone major systemic surgery ≤ 2 weeks prior to starting 
study drug or who have not recovered from side effects of such therapy. 
19. Participants who are pregnant or breastfeeding.   
20. Participants with history of known coagulopathy that increases risk of bleeding or a 
history of clinically significant hemorrhage within 12 months of start of study drug. 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
All sites should email the Study Coordinator at NeuroOnc_Coor@dfci.harvard.edu to verify slot 
availability.  
 
4.1 
General Guidelines for DF/HCC Institutions 
 
DF/HCC institutions will register eligible participants with the Clinical Trials Management 
System (CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. 
Any participant not registered to the protocol before protocol therapy begins will be considered 
ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed.   
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
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4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the DFCI Coordinating Center by a 
Coordinating Center team member.  All sites should email the Coordinating Center at 
NeuroOnc_Coor@dfci.harvard.edu to verify slot availability.  
 
The required forms can be found in Appendix B, Section 3.7.1.  Following registration, 
participants should begin protocol therapy as soon as feasible.  Issues that would cause treatment 
delays should be discussed with the Overall PI.  If a participant does not receive protocol therapy 
following registration, the participant’s registration on the study must be canceled.  The 
Coordinating Center should be notified of cancellations as soon as possible. 
 
4.4 
Registration Process for Other Investigative Sites 
 
To register a participant, please refer to Appendix B, Section 3.7.1.   
 
To complete the registration process, the Coordinator will follow DF/HCC policy (SOP #: 
REGIST-101) and register the participant on the protocol.  The coordinator will fax or e-mail the 
participant study number, and if applicable the dose treatment level to the participating site. 
 
5. TREATMENT PLAN 
 
Cohort 1 will be conducted concurrently with Cohort 2.   
 
5.1 
Treatment Regimen 
All participants will initiate treatment with abemaciclib as soon as feasible following registration.  
The study drug abemaciclib will be administered on an outpatient basis (except on day of surgery 
for Cohort 1 participants). The investigator will instruct the participant to take the study drug 
exactly as specified in the protocol. No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the patient’s malignancy.  
Abemaciclib will be administered on a continuous twice daily dosing schedule. Participants 
should be instructed to take the dose of 150 mg abemaciclib every 12 hours, with a minimum of 
6 hours between doses (for Cohort 1 pre-surgery abemaciclib should be taken as close to a 7AM 
– 7PM schedule as possible).  Cycle length will be 28 days for all Cohort 2 cycles, even if 
treatment is held mid-cycle for toxicity.  If a patient has not required dose reduction(s) due to 
toxicity during Cohort 2 Cycle 1, then the dose of abemaciclib may be escalated at the start of 
Cycle 2 to 200 mg every 12 hours if the investigator determines that it is in the best interest of 
the patient.  Abemaciclib should be taken with or without food at approximately the same times 
each day with a glass of water and consumed over as short a time as possible. Participants should 
swallow the tablets as a whole.  Abemaciclib tablets should not be opened, crushed, or chewed.  
Participants must avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, 
grapefruit hybrids, pomelos and exotic citrus fruits from 7 days prior to the first dose of study 
drug and during the entire study treatment period due to potential CYP3A4 interaction.   
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
25 
Instructions, including missed dose policy are included in the participant pill diary (Appendix E 
& F).  
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded. If a participant requires an abemaciclib dose delay of > 28 days from the 
previous dose, the participant must be discontinued from treatment completely. In the 
exceptional case where the investigator feels the patient would benefit from continuing therapy 
the case can be discussed with the Overall P.I. Eudocia Quant Lee, MD (617-632-2166). 
Expected toxicities and dose reductions and modifications are detailed in Section 6. 
If vomiting occurs during the course of treatment, no re-dosing of the participant is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be recorded as an adverse event. 
Missed doses should be taken immediately when the participant realizes the dose was missed. 
Although doses should ideally be 12 hours apart, a minimum of 6 hours is allowed between 
doses in case of a missed dose. If the participant forgets to take his/her abemaciclib dose more 
than 6 hours from the normally scheduled dosing time (i.e., less than 6 hours to the time of the 
next planned dose), then that dose should be withheld and abemaciclib should be restarted at the 
time of the next planned dose.  
Participants will keep a medication diary (see Appendix E & F). At the end of each cycle for 
Cohort 2 participants and after surgery for Cohort 1 participants, the diary will be returned and a 
new one will be given to the participant if continuing on therapy. Participants are to return all pill 
bottles and unused pills. 
 
5.2 
Cohort 1—Surgery Arm  
In Cohort 1, 15-20 eligible participants who require reoperation will be treated with abemaciclib 
for 10-14 days prior to surgery. The last dose should be on the day of surgery and taken 1-3 
hours prior to surgery and tumor removal.  Since participants in cohort 1 are undergoing PK 
testing, accurately recording the time of study drug administration on day of surgery and 
recording the time of tumor removal are especially important and required.  
In general, pre-operative, operative, and post-operative evaluations will consist of standard 
clinical practice. Required evaluations and research samples are detailed in Section 10. 
After surgery on study, cohort 1 participants will come off study treatment and pursue standard 
cancer treatments as per the treating physician’s discretion. Participants who enrolled on the 
surgical cohort before the surgical cohort was converted into a Phase 0, who have already started 
post-surgical abemaciclib dosing, and are benefitting from post-surgical abemaciclib treatment 
may remain on abemaciclib at the discretion of their treating physician and the approval of the 
overall PI, Dr. Eudocia Lee. These patients should instead follow the Study Calendar intended 
for Cohort 2 (nonsurgical) patients and their post-surgical C1D1 will represent C1D1 on the 
Cohort 2 study calendar.  
Following registration, Cohort 1 pre-surgical Day 1 subjects should be evaluated for eligibility to 
treat based upon dose modification criteria outlined in Table 6.3 and not General Eligibility 
Criteria outlined here in Protocol Section 3; General Eligibility Criteria outlined here in Protocol 
Section 3 need only be met during screening for trial. 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
26 
The goal is to have 15 eligible patients with adequate tissue for assessment of the primary 
objectives for this cohort. If sufficient tissue is not obtained for a patient enrolled in this cohort, 
the patient should continue treatment as originally intended and the clinical results reported. 
However, additional patients will be added to the cohort for the purpose of meeting the 
objectives related to tissue analysis. A maximum of 20 patients may be enrolled in this cohort. If 
the number of patients required to be replaced exceeds 5 consideration will be given to stopping 
enrollment to this cohort based on lack of feasibility.  
 
5.3 
Cohort 2—Treatment Arm  
Participants will be treated with abemaciclib every 12 hours until tumor progression or 
unacceptable toxicity. Cycle length will be 28 days, even if treatment is held mid-cycle for 
toxicity. Criteria for dose modifications and delays apply to intra-cycle administration and day 1 
administrations; there are no separate ‘start of cycle’ criteria; however Day 1 evaluations must be 
completed (and reviewed) before administration of study drug for that cycle (including C1D1).  
If a participant requires an abemaciclib dose delay of > 28 days from the previous dose, the 
participant must be discontinued from treatment completely. In exceptional cases where the 
investigator feels the patient would benefit from continuing therapy the case can be discussed 
with the Overall P.I. Eudocia Quant Lee, MD (617-632-2166). 
In general, participants will be required to come to clinic at the start of each cycle. Required 
evaluations and research samples are detailed in Section 10. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Participants must be instructed not to take any additional medications (including over-the-
counter products) during the trial without prior consultation with the investigator. All 
medications taken from date of consent up to 30-day post drug study visit (as detailed in Section 
10) should be recorded. If concomitant therapy must be added or changed, including over-the-
counter medications or alternative therapies, the reason and name of the drug/therapy should be 
recorded. 
 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
participant are allowed, including drugs given prophylactically (e.g. antiemetics) with the 
following exceptions: 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
27 
5.4.1 Abemaciclib is predominantly cleared by oxidative metabolism via CYP3A4.  Clinical 
drug interaction studies with a CYP3A inhibitor and CYP3A inducer significantly altered 
the PK of abemaciclib and its circulating major metabolites.  
• Avoid concomitant use of CYP3A inducers and consider alternative agents.  
• Avoid concomitant use of strong CYP3A inhibitors (for example, voriconazole) and 
use caution with coadministered moderate (for example, ciprofloxacin) or weak (for 
example, ranitidine) CYP3A inhibitors. If coadministration with a strong CYP3A 
inhibitor is unavoidable, reduce the abemaciclib dose to 100 mg twice daily or, in the 
case of ketoconazole, reduce the abemaciclib dose to 50 mg twice daily. In patients 
who have had a dose reduction to 100 mg twice daily due to adverse reactions, further 
reduce the abemaciclib dose to 50 mg twice daily. Avoid grapefruit or grapefruit 
juice. If a CYP3A inhibitor is discontinued, increase the abemaciclib dose (after 3-5 
half-lives of the inhibitor) to the dose that was used before starting the inhibitor.  
5.4.2 Caution should be exercised when co-administering abemaciclib with narrow therapeutic 
drugs that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, or 
CYP3A. Participants receiving such medications must be monitored for potentiation of 
toxicity due to any individual concomitant medications, and may require dose titration or 
reduction of the drug substrate. Please refer to Appendix D for a list of drugs. Please note 
that this list may not be comprehensive. 
5.4.3 Abemaciclib is an inhibitor of P-gp; therefore, caution should be exercised when 
coadministering abemaciclib with P-gp substrate drugs with narrow therapeutic index 
(e.g., digoxin). Abemaciclib may also inhibit the clearance of substrates of the renal 
transporter MATE1, such as endogenous creatinine and metformin. 
5.4.4 Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng. 
Participants should stop using any herbal medications 7 days prior to first dose of study 
drug. 
5.4.5 Corticosteroids should be used in the smallest possible dose to control symptoms of 
cerebral edema and mass effect, and discontinued if possible. Chronic dosing of 
corticosteroids is known to induce CYP3A enzymes, thereby increasing the risk of 
reducing abemaciclib drug exposure to sub-therapeutic levels. 
 
NOTE for Cohort 1: every effort should be made to not exceed a corticosteroid dose of 
> 4 mg/day between date of registration and on-study surgery.  If a corticosteroid of > 4 
mg / day is necessary for a participant following registration and prior to on-study 
surgery, the treating investigator should reach out to the Overall PI, Dr. Eudocia Quant 
Lee, to confirm the participant’s evaluability for tumor tissue studies.  
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
28 
5.4.6 Anti-seizure medications should be used as indicated. Only participants receiving non-
EIAEDs are eligible. If for unavoidable clinical reasons (emergency department visit, 
severe allergies, toxicities, etc.) a participant’s AED is switched to another AED, the 
following guidelines must be followed if applicable: 
o Participants should be started on another non-EIAED if at all possible.  
o Participants who are inadvertently and temporarily changed to an EIAED should 
immediately be changed to an alternative non-EIAED.  
o Participants who need to permanently change anticonvulsant, but who cannot 
change to another non-EIAED, must be discussed with the PI.  
5.4.7 Febrile neutropenia may be managed according to the local institution's guidelines. 
Measures may include appropriate laboratory testing, including blood and urine cultures 
and the institution of broad-spectrum antibiotics. If a source for the fever is not identified 
or the fever resolves when the neutrophil count recovers, antibiotics may be discontinued 
and the participant observed. 
5.4.8 G-CSF: Routine prophylactic use of G-CSF is not permitted. However, therapeutic use in 
participants with serious neutropenic complications, such as sepsis, may be considered at 
the investigator’s discretion. 
5.4.9 Antiemetics: The use of antiemetics will be left to the investigators’ discretion.  
5.4.10 Pneumocystis jirovecii pneumonia (PJP) prophylaxis: Since participants with malignant 
gliomas are at increased risk of developing PJP, especially if they are on corticosteroids, 
prophylaxis for PJP may be considered per institutional practice.  
5.4.11 Anticoagulants: Because of the potential for its interaction with study medications, 
warfarin sodium (Coumadin®), or any other coumadin-derivative anticoagulant, is not 
permitted at any dose. Low-molecular weight heparin and Xa inhibitors are permitted.  If 
for unavoidable clinical reasons (emergency department visit, severe allergy, toxicity, 
etc) a participant is started on Coumadin, they must change to a low molecular weight 
heparin immediately in the interest of subject safety. 
5.4.12 Surgery: If neurosurgical management is required for reasons not due to tumor 
progression, these procedures must be documented, including the indications for surgery, 
the operative note, and pathology report. 
5.4.13 Other Anticancer or Experimental Therapies: No other anticancer therapy of any kind is 
permitted during the study treatment period. No other drug under investigation may be 
used concomitantly with the study drug. 
5.4.14 Radiotherapy: No radiotherapy of any kind is permitted during the study treatment 
period. Limited data are available with abemaciclib and radiotherapy or alternate dosing 
schedules (e.g. induction phase). 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
29 
5.4.15 Other Concomitant Medications: Therapies considered necessary for the well-being of 
the participant may be given at the discretion of the investigator. Other concomitant 
medications should be avoided except for analgesics, chronic treatments for concomitant 
medical conditions, or agents required for life-threatening medical problems. All 
concomitant medications must be recorded. 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
• 
Cases of pregnancy that occur during maternal exposures to abemaciclib should be 
reported. If a patient or spouse/partner is determined to be pregnant following 
abemaciclib initiation, she must discontinue treatment immediately. Data on fetal 
outcome and breast-feeding are collected for regulatory reporting and drug safety 
evaluation. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF).  
 
When a participant is removed from protocol therapy and/or is off of the study, the participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Dr. Eudocia Quant Lee, at 617-632-2166.  
 
5.6 
Duration of Follow Up 
 
For all participants, off-treatment assessments are to be completed as described in Section 10.  
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
30 
A contact/visit to check for adverse events and vital status is to be performed at 30 days (+7 
days) after the last study drug is given.  This may be performed via documented phone 
conversation or in clinic with a study nurse or clinician. Content is further detailed in Section 10. 
 
All participants will be followed until resolution or stabilization of any serious adverse events 
occurring during treatment or starting within 30 days of last study drug. 
 
Participants who enter long-term follow-up will be followed via medical record review or 
contact (e.g., phone call) until death for post-treatment therapies, progression information, and 
survival. Each site will be responsible for collecting information on their participants regarding 
all post-treatment therapies, start and stop dates of those therapies, the reason for stopping those 
therapies, and the date of death. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure the 
participant’s status is updated in OnCore in accordance with DF/HCC policy REGIST-OP-1. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the participant on study drug. If administration of 
abemaciclib must be interrupted because of unacceptable toxicity, drug dosing will be 
interrupted or modified according to rules described in Table 6.3. 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
In the case of toxicity, appropriate medical treatment should be used (including anti-emetics, 
anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the 30 day post-study visit (see section 10). 
Participants continuing to experience toxicity at the end-of treatment visits may be contacted for 
additional assessments until the toxicity has resolved or is deemed irreversible.  
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
31 
All participants will be initially treated at Dose Level 0. 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
32 
 
    Table 6.0: Dose Levels 
 
Dose Level 
Dose of Abemaciclib 
1* 
200 mg every 12 hours 
0 
(starting dose) 
150 mg every 12 hours 
-1 
100 mg every 12 hours 
-2 
50 mg every 12 hours 
*If a patient has not required dose reduction(s) due to toxicity, then the dose of 
Abemaciclib may be escalated at the start of Cycle 2 to 200 mg every 12 hours if the 
investigator determines that it is in the best interest of the patient.   
 
6.1 
Anticipated Toxicities  
 
In order for an event to be expected (known correlation to study drug) for the purposes of 
adverse event reporting, the event must be included in this section.  
 
6.1.1 A list of adverse events of all grades suspected to be abemaciclib treatment related 
according to review of Investigator’s Brochure, organized by CTCAE v4.0 category, 
includes:   
 
• BLOOD & LYMPHATIC SYSTEM DISORDERS – White blood cell decreased, 
Neutrophil count decreased, Platelet count decreased, Anemia 
• EYE DISORDERS – Cataract  
• GASTROINTESTINAL – Diarrhea, Nausea, Vomiting, Dry mouth, Stomatitis 
• GENERAL DISORDERS – Fatigue 
• INFECTIONS & INFESTATIONS – Upper respiratory infection, lung infection, 
pharyngitis, urinary tract infection, conjunctivitis, sinusitis, vaginal infection, sepsis 
• INVESTIGATIONS – Creatinine increased, Weight loss, Aspartate aminotransferase 
increased, Alanine aminotransferase increased, GGT increased 
• METABOLISM & NUTRITION DISORDERS – Anorexia 
• MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – Muscular 
weakness 
• NERVOUS SYSTEM DISORDERS – Dysgeusia, Dizziness 
• RESPIRATORY, THORACIC & MEDIASTINAL DISORDERS – Pneumonitis 
• SKIN AND SUBCUTANEOUS TISSUE DISORDERS – Alopecia, Rash, Pruritis 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
33 
• 
VASCULAR DISORDERS – Thromboembolic event  
 
6.2 
Dose Modifications/Delays 
 
6.2.1 Table 6.3 should be adhered to for all toxicities considered at least possibly related to 
abemaciclib as noted below.  If a participant experiences a toxicity unlikely or unrelated 
to treatment with abemaciclib but may still warrant a hold or reduction of study drug for 
safety, discussion and approval by Overall Principal Investigator and Study Sponsor, 
Eudocia Quant Lee, MD is recommended. 
 
6.2.2 When treatment must be held pending resolution of toxicity to grade 1 or return to 
baseline, and the toxicity is a lab abnormality, in cases where participant had a pre-
existing laboratory abnormality at baseline, the toxicity can be considered “resolved” 
from a hold perspective when it has resolved to within 1 grade of the baseline value.  
NOTE: For the purposes of data entry, values from screening assessments should be 
entered in as ‘baseline’ values.   However, true “baseline values” - for the purpose of 
dose modifications on study, etc. - will be considered the last assessments/tests  
performed prior to initiation of study therapy. 
EXCEPTION: In instances where the value within 1 grade of the baseline value would 
still require a hold, continue to hold until resolution of toxicity to grade 1 or return to 
baseline. 
 
6.2.3 Participants who experience an adverse event that requires a treatment delay or dose 
reduction should be monitored with appropriate laboratory testing or other clinical 
evaluation at least weekly until resolution 
 
6.2.4 Following a dose delay which resumes mid cycle, day 1 procedures not associated with 
the adverse event do not need to be repeated. 
 
6.2.5 No more than 2 levels of dose reduction are permitted in this study. Participants cannot 
be treated below dose level -2. If a participant whose abemaciclib dose has been reduced 
by 2 dose levels requires another dose reduction, treatment on study must be stopped 
unless the participant has benefited from the study, in which case the investigator will 
contact the overall Principal Investigator, Dr. Eudocia Quant Lee, to determine if the 
participant will remain in the study. 
 
6.2.6 A treatment delay of up to 28 days is permitted. If the toxicity has not resolved after a 4-
week delay, the participant must be removed from study treatment unless the participant 
has benefited from the study, in which case the investigator may contact the Overall 
Principal Investigator, Dr. Eudocia Quant Lee, to determine if the participant will remain 
in the study. 
 
6.2.7 Dose re-escalation is never permitted in this study. 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
34 
6.2.8 Cycle length will be 4 weeks (28 days), even if treatment is held for toxicity. There is no 
stopping in counting cycles/days for those periods where a subject’s drug is withheld. All 
study evaluations and treatments should continue as if study treatment is not being held.  
 
6.2.9 If study drug is held across a time point which requires collection of a research blood 
sample, please contact the Sponsor Coordinating Center or Overall PI (Dr. Eudocia Quant 
Lee) to confirm whether or not the sample should be collected or if the drug hold will 
negate the value of collection of the sample in question.  If you anticipate the occurrence 
of such a scenario, please contact the Sponsor Coordinating Center as soon as possible in 
order to establish a plan prior to the time point in question.   
 
6.2.10 Participants whose treatment is interrupted or permanently discontinued due to an 
adverse event or clinically significant laboratory value, must be followed as outlined in 
Table 6.3, at least once a week for 4 weeks, and subsequently at 4-week intervals, until 
resolution or stabilization of the event, whichever comes first. All participants must be 
followed for adverse events and serious adverse events for 30 days following the last 
dose of abemaciclib. All SAEs must be reported as detailed in Section 7.4. 
 
Table 6.3: 
Criteria for dose-modification and re-initiation of abemaciclib treatment  
 
Table 6.3 should be adhered to for all toxicities considered at least possibly related to 
abemaciclib as noted below. If a participant experiences a toxicity unlikely or unrelated to 
treatment with abemaciclib but may still warrant a hold or reduction of study drug for safety, 
discussion and written approval by Overall Principal Investigator and Study Sponsor, Eudocia 
Quant Lee, MD is recommended. 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
35 
Toxicity 
(organized per CTCAE v 4.0) 
Actions 
Investigations (for hyperglycemia, see metabolism disorders) 
Unless otherwise specified, during duration of toxicity. 
General Guidance for Hepatic Monitoring 
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory test 
abnormalities. If a study patient experiences elevated ALT 5×ULN and elevated TBL 2×ULN, or ALT 8×ULN, liver 
tests, including ALT, AST, TBL, direct bilirubin, gamma glutamyl transferase (GGT), and creatine phosphokinase 
(CPK), should be repeated within 3 to 5 days to confirm the abnormality and to determine if it is increasing or 
decreasing.  If the abnormality persists or worsens, clinical and laboratory monitoring should be initiated by the 
investigator, based on the hepatic monitoring tests below. 
Hepatic Hematology 
Haptoglobin 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulation 
RBC 
Prothrombin Time 
WBC 
Prothrombin Time, INR 
Neutrophils, segmented and bands 
 
Lymphocytes 
Hepatic Serologiesa 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B Core antibody 
Hepatic Chemistry 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear antibody 
AST 
Anti-actin antibody 
GGT 
CPK  
Anti-smooth muscle antibody 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells. 
a Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
ALT/SGPT or AST/SGOT  
- Grade 2 (>3.0- 5.0 x ULN) 
WITHOUT increase in total 
bilirubin above 2 x ULN 
First Occurrence: 
Interrupt until resolution to ≤ grade 1, then 
• 
If resolution to grade ≤1 in ≤ 7 days, resume ABEMACICLIB at the 
current dose level  
• 
If resolution to ≤ grade 1 takes > 7 days, resume ABEMACICLIB at one 
lower dose level  
 
Second/Third Occurrence: 
Interrupt until resolution to ≤ grade 1, then resume ABEMACICLIB at one lower 
dose level 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
36 
ALT/SGPT or AST/SGOT 
- Grade 3 (> 5.0 - 20.0 x 
ULN) 
 
First Occurrence: 
Interrupt until resolution to ≤ grade 1, then 
• 
If resolution to grade ≤1 in ≤ 7 days, resume ABEMACICLIB at the 
current dose level  
• 
If resolution to ≤ grade 1 takes > 7 days, resume ABEMACICLIB at one 
lower dose level  
Once resolved to ≤ grade 1, monitor liver function tests every other week or 
more frequently if clinically indicated until the end of treatment with study 
medication. 
 
Second/Third Occurrence: 
Interrupt until resolution to ≤ grade 1, then resume ABEMACICLIB at one lower 
dose level 
 
Once resolved to ≤ grade 1, monitor liver function tests every other week or 
more frequently if clinically indicated until the end of treatment with study 
medication. 
 
ALT/SGPT or AST/SGOT 
- Grade 3 (> 5.0 - 20.0 x 
ULN) WITH increase in total 
bilirubin above 2 x ULN in 
the absence of cholestasis 
 
Discontinue abemaciclib. 
ALT/SGPT or AST/SGOT  
- Grade 4 (>20.0 x ULN)  
Discontinue abemaciclib.  
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
37 
General Guidance for Increases in Serum Creatinine and Assessment of Renal Insufficiency 
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular transporters 
without affecting glomerular function (as measured by iohexol clearance). In clinical studies, increases in serum 
creatinine occurred within the first month of abemaciclib dosing, remained elevated but stable through the 
treatment period, were reversible upon treatment discontinuation, and were not accompanied by changes in 
markers of renal function, such as blood urea nitrogen (BUN), cystatin C, or calculated glomerular filtration rate 
based on cystatin C. 
Creatinine  
- Grade 2 (>1.5 - 3 x ULN) 
Maintain treatment with ABEMACICLIB 
Creatinine  
- Grade 3 (> 3.0 - 6.0 x ULN) if 
believed deterioration of renal 
function is suspected (as 
evidenced by changes in other 
markers of renal function, such 
as BUN, cystatin C, or calculated 
GFR based on cystatin C). 
 
Interrupt treatment until resolution to ≤ grade 1 or returned to baseline, 
treatment may resume at the same dose level or a 1 dose level decrease, at 
the investigator’s discretion.  Continuation of ABEMACICLIB is permitted 
upon recovery to stable Grade 2 if the investigator and overall principal 
investigator (Dr. Eudocia Quant Lee) agree that the event is not considered 
clinically significant. 
Creatinine  
- Grade 4 (> 6.0 x ULN) if 
believed deterioration of renal 
function is suspected (as 
evidenced by changes in other 
markers of renal function, such 
as BUN, cystatin C, or calculated 
GFR based on cystatin C)    
Discontinue ABEMACICLIB 
General Guidance for Hematology Toxicity and Dose Modification 
Hematologic toxicities including neutropenia, leukopenia, anemia, and thrombocytopenia have been observed 
in patients treated with abemaciclib, and causality has been established.  Severe (Grade 3 and 4) neutropenia 
was observed in patients receiving abemaciclib.  Patients should be monitored closely for signs of infection, 
anemia, and bleeding. 
Anemia 
- Grade 3 (Hgb <8.0 g/dL; <4.9 
mmol/L; <80 g/L; transfusion 
indicated) 
First Occurrence: 
Interrupt until resolved to ≤ grade 2, then resume ABEMACICLIB at the 
current dose level 
 
Second Occurrence: 
Interrupt until resolution to ≤ grade 2, then resume ABEMACICLIB at one 
lower dose level 
Anemia 
- Grade 4 (Life-threatening 
consequences; urgent 
intervention indicated) 
Interrupt until resolution to ≤ grade 2, then resume ABEMACICLIB at one 
lower dose level 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
38 
Patient requires administration 
of a blood cell growth factor 
Suspend abemaciclib dose for at least 48 hours after the last dose of blood 
cell growth factor and until toxicity resolves to ≤Grade 2. 
Resume abemaciclib at next lower dose unless the dose was already 
reduced for the toxicity that led to the use of the growth factor. 
Neutropenia  
- Grade 3 (ANC < 1.0 - 0.5 x 
109/L) 
First Occurrence: 
Interrupt until resolved to ≤ grade 2, then resume ABEMACICLIB at the 
current dose level 
 
Second Occurrence: 
Interrupt until resolution to ≤ grade 2, then resume ABEMACICLIB at one 
lower dose level 
Neutropenia  
- Grade 4 (ANC < 0.5 x 109/L) 
Interrupt until resolution to ≤ grade 2, then resume ABEMACICLIB at one 
lower dose level 
Patient requires administration 
of a blood cell growth factor 
Suspend abemaciclib dose for at least 48 hours after the last dose of blood 
cell growth factor and until toxicity resolves to ≤Grade 2. 
Resume abemaciclib at next lower dose unless the dose was already 
reduced for the toxicity that led to the use of the growth factor. 
Thrombocytopenia  
- Grade 3 (<50-25 x 109/L  PLT) 
First Occurrence: 
Interrupt until resolved to ≤ grade 2, then resume ABEMACICLIB at the 
current dose level 
 
Second Occurrence: 
Interrupt until resolution to ≤ grade 2, then resume ABEMACICLIB at one 
lower dose level 
Thrombocytopenia  
- Grade 4 (PLT < 25 x 109/L ) 
Interrupt until resolved to ≤ grade 2, then resume ABEMACICLIB at one 
lower dose level 
 
Patient requires administration 
of a blood cell growth factor 
Suspend abemaciclib dose for at least 48 hours after the last dose of blood 
cell growth factor and until toxicity resolves to ≤Grade 2. 
Resume abemaciclib at next lower dose unless the dose was already 
reduced for the toxicity that led to the use of the growth factor. 
Gastrointestinal Disorders 
Guidelines for Diarrhea Management 
Clinical trial data indicates the majority of patients who receive abemaciclib will develop diarrhea. Our 
experience indicates early identification and intervention for the management of diarrhea has been helpful to 
patients.  
At enrollment, patients should receive instructions on the prompt management of diarrhea. In the event of 
diarrhea, supportive care measures should be initiated as early as possible.  These include the following: 
• 
At the first sign of loose stools, the patient should initiate antidiarrheal therapy (e.g. loperamide) and 
notify the investigator for further instructions and appropriate follow up. 
• 
Patients should also be encouraged to drink fluids (e.g., 8 to 10 glasses of clear liquids per day). 
• 
Site personnel should assess response within 24 hours.  
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
39 
Diarrhea  
- Grade 2 (4-6 stools/day > 
pretx) 
 
If diarrhea can be controlled with optimal anti-diarrheal treatment within 24 
hours to either baseline or grade 1, continue ABEMACICLIB. If not, interrupt 
treatment until resolved to ≤ grade 1, then resume ABEMACICLIB at the 
current dose (treating investigators may reduce by 1 dose level at their own 
discretion for first occurrence). If diarrhea persists or returns as ≥ grade 2, 
then interrupt treatment until resolved to ≤ grade 1, then resume 
ABEMACICLIB at one lower dose level. 
Diarrhea 
- Grade 3 (7-9 stools/day > 
pretx) 
- Grade 4 (≥ 10 stools/day > 
pretx) 
(requires hospitalization) 
 
If diarrhea can be controlled with optimal anti-diarrheal treatment within 24 
hours to either baseline or grade 1, continue ABEMACICLIB. If not, for 
diarrhea ≥ Grade 3 or requires hospitalization, interrupt treatment until 
resolved to ≤ grade 1, then resume ABEMACICLIB at one lower dose level. 
Respiratory, Thoracic, and Mediastinal Disorders 
General Guidance for Interstitial lung disease (ILD)/Pneumonitis events 
Interstitial lung disease (ILD) / pneumonitis has been identified as an adverse drug reaction for abemaciclib. 
Adverse events reported included events such as interstitial lung disease, pneumonitis, obliterative 
bronchiolitis, organizing pneumonia, pulmonary fibrosis. The majority of events were Grade 1 or Grade 2 with 
serious cases and fatal events reported.  
 
Monitor for clinical symptoms or radiological changes indicative of ILD/pneumonitis and please ask patients to 
report any new or worsening pulmonary symptoms. Symptoms may include hypoxia, cough, dyspnea, or 
interstitial infliltrates on radiologic exams.; these symptoms should be investigated and treated as per local 
clinical practice and/or guidelines (including corticosteroids as appropriate). Infectious, neoplastic, and other 
causes for such symptoms should be excluded by means of appropriate investigations. Investigations may 
include imaging such as high resolution computer tomography (HRCT), broncheoalveolar lavage (BAL), and 
biopsy as clinically indicated (see also Table 7: refer to dose adjustment table for interstitial lung 
disease/pneumonitis). 
Grade 1 or 2  
Maintain treatment with ABEMACICLIB 
Persistent or recurrent Grade 2 
toxicity that does not resolve 
with maximal supportive 
measures within 7 days to 
baseline or Grade 1 
Interrupt until resolution to ≤ grade 1 or baseline, then resume 
ABEMACICLIB at one lower dose level 
Grade 3 or 4 
Discontinue ABEMACICLIB 
Other unspecified RELATED adverse events 
Other unspecified Grade 1 and 2 
events considered at least 
possibly related to 
ABEMACICLIB 
Maintain treatment with ABEMACICLIB 
Other unspecified persistent or 
recurrent Grade 2 events 
Interrupt until resolution to ≤ grade 1 or baseline, then resume 
ABEMACICLIB at one lower dose level 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
40 
considered at least possibly 
related to ABEMACICLIB that 
dose not resolve with maximal 
supportive measures within 7 
days to baseline or Grade 1 
Other unspecified Grade 3  or 4 
events considered at least 
possibly related to 
ABEMACICLIB 
Interrupt treatment until resolution to ≤ grade 1 or baseline, then resume 
ABEMACICLIB at one lower dose level.  Continuation of ABEMACICLIB is 
permitted upon recovery to stable Grade 2 if the investigator and overall 
principal investigator (Dr. Eudocia Quant Lee) agree that the event is not 
considered clinically significant. 
 
 
Other unspecified UNRELATED adverse events 
Other unspecified events of any 
grade considered unlikely to be 
related or not related to study 
drug. 
Maintain treatment with ABEMACICLIB.  Interruption of ABEMACICLIB is 
permitted at the treating investigator’s discretion. It is recommended that 
the investigator consults with the overall principal investigator (Dr. Eudocia 
Quant Lee) to determine that this is in the interest of the participant.  
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.2) and the characteristics of an 
observed AE (Section 7.3) will determine whether the event requires expedited reporting in 
addition to routine reporting in the study specific database. 
 
7.1 
General Information and Periods of Observation, Recording and Reporting 
 
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or mother means, will be collected, recorded, 
followed and reported as described in the following sections.  
 
Adverse events experienced by participants will be collected and recorded from the first dose of 
study treatment until 30 days after the last dose of study medication.  The period for collection 
and recording of adverse events is extended for participants with ongoing reportable adverse 
events (protocol section 7.4) at least possibly related to study agent; for such participants, 
adverse events will be followed until the reportable event has resolved, stabilized, or determined 
to be irreversible by the reporting investigator.  The Coordinating Center should be consulted 
prior to ending the follow-up of events that have stabilized.  
 
7.1.1 Definitions 
 
7.1.1.1 
Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after beginning study treatment, even 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
41 
if the event is not considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests.  
 
7.1.1.2 
Serious Adverse Event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that: 
• Results in death 
• Is life-threatening. Life-threatening means that the person was at immediate 
risk of death from the reaction as it occurred (i.e., it does not include a 
reaction with hypothetically might have caused death had it occurred in a 
more severe form) 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least 
a 24-hour hospitalization or prolonged a hospitalization beyond the expected 
length of stay).   
• Results in persistent or significant disability/incapacity. Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life 
functions.  
• Is a congenital anomaly or birth defect; or,  
• Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; blood dyscrasias or convulsions that do not 
result in participant hospitalization, or the development of drug dependency or 
drug abuse.  
 
7.2 
Expected Toxicities 
 
7.2.1 Adverse Events List(s) 
 
7.2.1.1 
Adverse Event List(s) for Abemaciclib 
 
Expected adverse events are those that have been previously identified as resulting 
from administration of the agent.  For the purposes of this study, an adverse event 
is considered expected when it appears in the Anticipated Toxicities list (protocol 
section 6.1.1) which is derived from the Investigator’s Brochure.  
 
7.3 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
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to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.4 
Expedited Adverse Event Reporting  
 
7.4.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form.  
 
7.4.2 For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical event equivalent to an 
unexpected grade 2 or 3 with a possible, probable or definite attribution, unexpected 
grade 4 toxicities (unless specifically listed in this protocol as not requiring reported), and 
all grade 5 (death) regardless of study phase or attribution. 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

 
 
 
43 
 
7.4.3 Expedited Reporting Guidelines to DFCI Coordinating Center & Lilly  
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human Research Studies (OHRS) per the DFCI 
IRB reporting policy.  Other investigative sites outside of DF/HCC will report AEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the AE form should be forwarded to the Overall PI within the 
timeframes detailed in the table below. The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according 
to DFCI IRB policies and procedures in reporting adverse events.  
In addition to local IRB reporting policies, all sites are required to following the below expedited reportable AE requirements: 
 
Adverse Event Characteristics 
Reporting Requirement 
Serious- 
ness 
Toxicity 
Known Correlationf 
Attribution to 
Abemaciclib 
Eli Lilly and Company 
- 
Via Emailc  
Use Reportable AE Coversheet c and 
Medwatch 3500A d 
Overall PI (Eudocia Lee, MD) at the 
DFCI Coordinating Center  
Via Email b 
Use Reportable AE Coversheet c and 
Medwatch 3500A d  
Seriouse 
Any 
Any 
(Expected or 
Unexpected) 
Any 
Within 15 business days from 
notification a 
 
Within 24 hours from notification a 
 
Non-
Serious 
Grade 4  
Unexpected 
Any 
Not Required 
Within 5 calendar days from 
notification a 
Non-
Serious 
Grade 2 or 3 
Unexpected 
Possible, Probable, or 
Definite 
Not Required 
Within 5 calendar days from 
notification a 
a. 
In the event that the participating investigator/site team does not become aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator/site team is to report the event within required hours/days noted above after learning of it and document the time of his or her first awareness of the 
adverse event. 
b. 
Email the Medwatch 3500A form, reportable AE coversheet (Appendix C), and the local IRB SAE report (if applicable) to the DFCI Coordinating Site with the subject title as 
“Abemaciclib SAE” to NeuroOnc_SAE@dfci.harvard.edu.  All SAE reports received at this account are forwarded immediately to study’s Overall PI, Dr. Eudocia Quant Lee, and 
to the DFCI Coordinating Center personnel.  
c. 
Reportable AE Coversheet is found in Appendix C.  The coversheet contains all e-mails and needed for reporting purposes.   
d. 
Medwatch 3500A downloadable form at  http://www.fda.gov/medwatch/getforms.htm 
e. 
Seriousness is defined in section 7.1.1.2 
f. 
Expected adverse events are those that have been previously identified as resulting from administration of the agent.  For the purposes of this study, an adverse event is 
considered expected when it appears in the Anticipated Toxicities list (protocol section 6.1.1) which is derived from the Investigator’s Brochure. 
Dana Farber
IRB NUMBER: 16-383
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7.4.4 How to report AEs to Lilly & DFCI Coordinating Center/Overall PI 
 
1. Document/describe AE on each of the following: 
a. MedWatch 3500A  
i. downloadable form at http://www.fda.gov/medwatch/getforms.htm  
b. DFCI Coordinating Center Reportable AE Coversheet 
i. AE Coversheet is found in Appendix C.  A modifiable Microsoft Word 
document is also available from the DFCI Coordinating Center.   
 
2. To report to DFCI Coordinating Center/Overall PI 
a. Scan and email completed Reportable AE Coversheet and MedWatch to 
NeuroOnc_SAE@dfci.harvard.edu with the subject title as “Abemaciclib 
SAE” 
b. All AE reports received at this account are forwarded immediately to the 
Overall PI (Dr. Eudocia Quant Lee), and to DFCI Coordinating Center 
personnel 
c. If available and applicable, please also include the local IRB submission for 
this event in the submission to the DFCI Coordinating Center. 
 
3. To report to Eli Lilly and Company 
a. Scan and email completed Reportable AE Coversheet and MedWatch to 
MAILINDATA_GSMTINDY@LILLY.COM and copy the DFCI Coordinating Center 
(NeuroOnc_SAE@dfci.harvard.edu) 
 
NOTE: When reporting events to both Eli Lilly and DFCI, one e-mail can be sent to all 
parties simultaneously. 
 
7.4.5 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB.  However, they still must be reported through the routine 
reporting mechanism (i.e. case report form). 
 
Events not considered to be serious adverse events for this protocol are: 
• Lymphopenia (grade 2-4) 
• Hospitalization for routine treatment or monitoring of the studied indication, 
not associated with any deterioration in condition, or for elective procedures 
(including off-treatment hospitalization for re-resection within 30-days of last 
dose of study drug to treat progressive disease) 
• Hospitalization for elective or pre-planned treatment for a pre-existing 
condition that did not worsen since beginning study drug 
• Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
• Hospitalization for seizure, related to GBM (disease under study) and 
unlikely/unrelated to study treatment 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
45 
 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.6 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 6.1.1. 
 
8.1 
Abemaciclib 
 
8.1.1 Description 
 
The chemical name is: [5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-
fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine. 
Abemaciclib is also known as LY2835219 and is a selective, potent small molecule 
CDK4/6 dual inhibitor. The molecular weight is 506.60. 
 
In humans, the terminal elimination half-life (t1/2) in plasma ranges from approximately 
17 to 38 hours. Following oral administration, abemaciclib was extensively metabolized 
followed by biliary excretion of metabolites. Strong CYP3A inhibitors may increase 
abemaciclib exposures, and strong inducers may decrease abemaciclib exposures. 
Caution should be exercised when coadministering abemaciclib with narrow therapeutic 
drugs that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, or 
CYP3A. 
 
8.1.2 Form 
 
Abemaciclib drug product will be supplied for clinical trial use as abemaciclib with 
excipients in tablets. The drug products are stable when stored according to instructions 
Dana Farber
IRB NUMBER: 16-383
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A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
46 
on the label. 
 
50 mg Abemaciclib tablets will be supplied as a modified oval, immediate-release, 
aqueous, film-coated abemaciclib tablet containing 50 mg of abemaciclib and the 
following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, silicon dioxide, sodium stearyl fumarate, and color mixture 
beige. 
 
8.1.3 Storage and Stability 
 
Abemaciclib is stable when stored according to the instructions on the label. 
 
8.1.4 Compatibility 
 
There are no known compatibility issues. 
 
8.1.5 Handling 
 
Routine chemotherapy handling is recommended.  
 
8.1.6 Availability 
 
Abemaciclib is an investigation agent and will be supplied free-of-charge from Lilly 
Pharmaceuticals. 
 
8.1.7 Preparation 
 
None 
 
8.1.8 Administration 
 
o Abemaciclib will be administered at a starting dose of 150 mg every 12 hours. If a 
patient has not required dose reduction(s) due to toxicity, then the dose of 
Abemaciclib may be escalated at the start of Cycle 2 to 200 mg every 12 hours if 
the investigator determines that it is in the best interest of the patient.  Doses 
should be spaced approximately 12 hours apart, with a minimum of 6 hours 
between doses.  Abemaciclib should be taken with or without food at 
approximately the same times each day with a glass of water.. Participants should 
be instructed to take their doses, twice a day, at approximately the same times 
each day and approximately 12 apart (for Cohort 1 pre-surgery abemaciclib 
should be taken as close to a 7AM – 7PM schedule as possible), except on the 
days of the pharmacokinetic sampling at which time the participant should be 
instructed to not take their morning abemaciclib dose until after their clinic visit. 
For Cohort 1 pre-surgery abemaciclib, the last dose should be on the day of 
surgery 1-3 hours prior to surgery and tumor removal.  Since participants in 
Cohort 1 are undergoing PK testing, accurately recording the time of study drug 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
47 
administration on day of surgery and recording the time of tumor removal is 
especially important.  
o If vomiting occurs during the course of treatment, no re-dosing of the participant 
is allowed before the next scheduled dose. The occurrence and frequency of any 
vomiting during a treatment cycle must be recorded as an adverse event.  
o If the participant forgets to take his/her abemaciclib dose more than 6 hours from 
the participant’s normally scheduled dosing time (i.e., less than 6 hours to the 
time of the next planned dose), then that dose should be withheld and abemaciclib 
should be restarted at the time of the next planned dose.  
 
8.1.9 Ordering 
 
Drug supply will be ordered from Eli Lilly by site pharmacy personnel. A form, with 
drug information and email address for submission, will be supplied to each institution’s 
pharmacy by the coordinating center once local IRB approval is received.  Anticipate 3-5 
business days to receive drug after the order is placed. 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.11 Destruction and Return 
 
Abemaciclib will be destroyed on site according to institutional policies, documented in 
the Drug Accountability Record Form. At the time of expiration / study close, a drug 
disposition form provided by Lilly Pharmaceuticals Inc. will be sent out to be signed off 
by the Pharmacist and Investigator verifying the destruction of drug.  
 
 
 
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IRB NUMBER: 16-383
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Version 4.0 – July 13, 2021 
 
48 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Several biomarker and correlative studies are planned for this study. 
 
9.1 
Biomarker Studies from Any Prior Surgery 
 
Eligibility for registration will be dependent on prior tumor being profiled by genomic methods 
that are sufficient for determination of the copy and mutation status of CDKN2A/B/C, RB1, and 
CDK4/6. Data can be generated from any prior tumor surgery. This data will not be generated as 
part of the trial process but will be pre-existing data. All data must be performed in a CLIA-
certified laboratory. Central molecular pathology review will be performed and may include 
reports or raw data as needed to determine the status of relevant loci. Commonly used tests 
include: 
 
1. OncoCopy Whole Genome Array CGH (DFCI/BWH) 
2. OncoPanel Targeted Exome Sequencing (DFCI/BWH) 
3. FoundationOne testing (Foundation Medicine) 
4. Other sequencing and copy data (e.g. TGEN) 
5. IMPACT sequencing and copy (MSKCC) 
 
Data will be evaluated for:  
 
1. Presence of CDKN2A, CDKN2B, CDKN2C loss equivalent to a loss greater than 1 copy 
of any one or more of these genes. Entry based on single copy loss will be allowed only 
in the event of a concurrent SNV present which is deemed likely damaging/inactivating 
by literature and database review. 
 
AND 
 
2. Absence of any copy, SNV, indel, or other aberration deemed likely inactivating in the 
RB1 gene. These would include non-sense mutations with truncation of protein, or 
homozygous (>1 copy) loss by copy analysis. 
 
9.2 
Laboratory Correlative Studies 
 
Correlative studies and tissue required for these are mandatory for all participants with the 
exception of specified imaging studies.  
 
Correlative study time points are included in Section 10 (Required Activity Calendar). 
 
NOTE: Study Sponsor, or his/her designee, may ultimately opt to not pursue analysis of one or 
more of the correlative studies specified in the protocol if the study is not positive and/or the data 
gained from the analysis is no longer believed to be helpful. 
 
Cohort 1: In this cohort, patients with recurrent GBM will receive drug for 10-14 days prior 
surgery, abemaciclib should be taken as close to a 7AM – 7PM schedule as possible during pre-
Dana Farber
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A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
49 
surgery cycle. The last dose should be on the day of surgery 1-3 hours prior to surgery and tumor 
removal. 
 
During surgery, tumor tissue and plasma will be collected simultaneously. Planned analyses for 
resected tumor tissue as follows: 
 
1) Frozen tumor samples and plasma samples will be evaluated for drug concentration using 
liquid chromatography - tandem mass spectrometry (LC-MS/MS) to derive a 
tumor/plasma ratio. Tumor concentration will be compared to plasma drug concentrations 
to determine if therapeutic levels of abemaciclib can be achieved in both enhancing and 
non-enhancing tumor.  
 
2) Frozen tumor samples, archival and study surgery FFPE tumor tissue will be evaluated for 
drug target pathway dysfunction and for pharmacodynamic alterations of signal transduction 
molecules relevant to the response to abemaciclib. Tumor tissue will be analyzed by IHC 
and proteomics studies for pRb (S807/811), proliferation (e.g. Ki-67), and apoptosis (e.g. 
cleaved caspase 3) to determine if abemaciclib can achieve a pharmacodynamic effect in 
enhancing and non-enhancing tumor tissue. These data will be compared to similar 
analyses performed on tumor tissue not exposed to abemaciclib obtained from each 
participant’s prior surgery, and from tumor specimens from untreated glioblastoma 
patients who undergo reoperation as part of another ongoing study (ABTC 1301: 
MLN0128 in recurrent glioblastoma).  
 
3) Fresh-preserved tumor tissue and/or whole blood will be evaluated for the drug’s 
immunostimulatory effects based on the following immunological assays: 
o TIL Density and TCR Overlap:  We will evaluate whether next generation 
sequencing of the T cell receptor (TCR) repertoire within GBM tissue and blood 
can identify shared TCRs, which can then effectively track anti-tumor immune 
responses induced by abemaciclib. Genomic DNA will be isolated from fresh-
frozen tumor (protocol surgery) and peripheral blood (immune monitoring 
timepoints) and subjected to next generation sequencing through the TCRVβ 
region to quantify TIL density and assess the overlap between tumor and 
peripheral blood. The TIL density and TCR overlap will then be correlated with 
clinical variables to identify potential biomarkers with prognostic and predictive 
value for outcomes (ORR, PFS, OS and toxicity). The TIL density and TCR 
overlap will be performed at Adaptive Biotechnologies (Seattle, WA).  
Investigators at the UCLA Brain Tumor Immunology Research Laboratory will 
perform analysis. Guidance on peripheral blood collection, processing and 
shipping is provided in Table 9.2 below. 
o Immunological multiplex immunofluorescence (IF) measurements: a minimum of 
10 FFPE unstained sections from the protocol surgery are to be submitted per 
Table 9.2 below. Multiplex IF will be performed to assess the proportion of tumor 
infiltrating lymphocytes (TIL) with PD-1 expression and delineation of PD-L1 
expression on GFAP+ tumor cells versus myeloid cells (CD45+) within the tumor 
microenvironment. 
o Peripheral Blood Immunophenotyping: The absolute lymphocyte count and 
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IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
50 
proportion of specific lymphocyte subsets will be quantified at each time point. 
Using a mass cytometry (CyToF) antibody panel analysis, lymphocyte/leukocyte 
subsets, activation markers, and negative costimulatory molecules will be 
evaluated before and after administration of abemaciclib.  Lineage markers for 
immune cell populations, activation markers, memory/antigen experience 
markers, and exhaustion markers will be stained with an established 24 antibody 
CyToF panel.  Analysis will be done using CyToF Kit and Phenograph, and 
clusters subsequently downloaded as .fcs files for analysis using FloJo.  CyToF 
analysis will be performed on PBMC obtained from Ficoll density gradient 
separation of whole blood. Blood draws for this testing will be done pre-treatment 
and on the day of surgery prior to dosing. Guidance on peripheral blood 
collection, processing and shipping is provided in Table 9.2 below. 
o Gene expression signatures and somatic mutations: Tumor samples from the 
protocol surgery should be immersed in Allprotect tissue reagent solution 
(Qiagen) or RNA-later® reagent and shipped to the UCLA Brain Tumor Research 
Laboratory.  Exome sequencing (tumor/PBMC) and RNA Seq will be performed 
at the UCLA GenoSeq Core facility and analyzed. We will assess the number of 
somatic mutations and potential neoantigens in each tumor using a new UCLA-
developed pipeline (veraT) and this data will be correlated with clinical variables 
to identify potential biomarkers with prognostic and predictive value for outcomes 
(ORR, PFS, OS). We will also develop immune signatures with the sequencing 
data and evaluate whether the presence of a pre-existing immune signature can 
also be correlated with clinical variables. 
 
4) Frozen tumor tissue from protocol surgery will be characterized using single-cell RNA-
sequencing using the SMART-Seq2 protocol to analyze the transcriptional profile of 
tumor cells treated with abemaciclib, allowing us to identify differences in cellular 
programs in comparison to historical untreated controls. Single-cell suspensions from 
frozen will be sorted based on CD45 expression and markers of cell integrity and 
viability and sorted into 96-multiwell plates containing cell lysis buffer. We plan to bank 
15 plates of CD45-negative (primarily malignant cells) and 5 plates of CD45+ (primarily 
immune) cells per specimen with this method. 
 
5) FFPE tumor tissue from protocol surgery will be evaluated for tissue microenvironment 
using multiplexed IF. The goal is to determine the tumor’s immunological state and the 
immune milieu of the tumor microenvironment with respect to MHC and other markers.  
 
6) We will also perform additional novel PK determinations using Maldi Mass Spec 
methods developed by Dr. Nathalie Agar (DFCI/BWH), which will be performed on 
frozen surgical specimens with excess tissue not needed for conventional methods of PK 
determination. 
 
7) We will attempt to establish patient derived cells (PDC), cell lines/xenografts 
(PDCL/PDX) from patients on treatment with the goal to compare effects of abemaciclib 
on models to the patient response. 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
51 
Cohort 1 Tumor Tissue Designation  
 
Please note that surgery should be performed Sunday-Thursday to accommodate overnight 
shipment of tissues designated for immunologic assay for receipt by UCLA Monday-
Friday (as UCLA will not accept samples on Saturday or Sunday). Before shipping any 
samples, please confirm the lab’s receiving availability. 
 
Four tissue samples (each at least 200mg) of the tumor will be collected from the contrast-
enhancing (CE) area of the tumor and placed into individual cryovials labeled 1 (CE-PK), 
2 (CE-PD), 5 (CE-IM), and 6 (CE-RNA). If deemed medically safe and feasible, two 
additional tissue samples (each at least 200mg) will be collected from a non-contrast-
enhancing (NCE) area of the tumor and placed into individual cryovials labeled 3 (NCE-
PK) and 4 (NCE-PD). 
 
The tubes labeled 1 (CE-PK) and 3 (NCE-PK) will be used for pharmacokinetic/drug 
concentration measurements. The tubes labeled 2 (CE-PD) and 4 (NCE-PD) will be used 
for pharmacodynamic protein analysis for determination of modulation of the targeted 
pathway, and/or for nucleic acid extraction and genomic analysis (array CGH, sequencing). 
The tube labeled 5 (CE-IM) will be used for immunologic correlatives. The tube labeled 6 
(CE-RNA) will be used for transcriptional profiling via single-cell RNA-sequencing. 
 
Every effort should be made to collect adequate amounts of tissue as this is a primary 
objective of the study. On average, each 200mg specimen should be approximately 0.5 cm3 
in volume (size of a large green pea). In the event of inadequate tissue to meet the 
minimum requirements, the maximum amount of tissue available should be collected and 
submitted within the tube labeled 1 (CE-PK) or 3 (NCE-PK).  
 
Portions of the tissue should be analyzed by frozen section or smear preparation by a 
pathologist or designated assistant to confirm viability and presence of >50% tumor nuclei 
in the tissue samples submitted (<30% necrosis). Tissue viability will ultimately also be 
confirmed by the central neuropathology team at the DFCI Coordinating Center.  
 
Once confirmed and allocated to the proper tubes, all tissue samples EXCEPT for the tubes 
labeled 5 (CE-IM) and 6 (CE-RNA) should be snap frozen and stored at the local site at -
70 degrees Celsius or lower temperature until the local pathologist has finalized the clinical 
diagnosis and confirmed that tissue is no longer required for diagnosis. Tissue for the 
immunologic studies labeled 5 (CE-IM) should be fresh preserved tissue. Tissue labeled 6 
(CE-RNA) should be frozen on dry ice without OCT or LN2. 
 
If more tissue is available, an additional 200mg or larger sample should be sent fresh to the 
appropriate hospital research lab for establishment of a participant primary cell line (serum 
free, neurosphere methods) by the site’s standard procedures. All remaining tissue from the 
resection should then be processed in a routine manner (formalin fixation and paraffin 
embedding) for clinical pathologic interpretation. 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
52 
Both types of tissue (fresh tissue and FFPE) will be processed for correlative studies. 
Samples for tissue PK analysis should be sent to the Pharmacoanalytical Shared Resource, 
under the direction of Dr. Mitch Phelps at The Ohio State University (OSU). Samples for 
tissue PD analysis and tissue microenvironment should be sent to Dr. Keith Ligon at DFCI. 
Samples for immunologic assays should be sent to Dr. Robert Prins at UCLA.  
 
Pharmacokinetic (PK) Samples: 
 
Once local collection and analysis are complete, tissue samples for PK analysis [tubes 
labeled 1 (CE-PK), 3 (NCE-PK)] should be shipped to the address below approximately 30 
days after surgery.   
 
Preparing the shipment 
E-mail the DFCI Coordinating Center at NeuroOnc_Coor@dfci.harvard.edu at least 24 
hours prior to shipment of samples to confirm the receiving lab is aware of the shipment.  
 
Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH).  
• Organize the samples by patient and timepoint in the box.  
• Do not store in plastic bags (they break on dry-ice and labels will detach).  
• A copy of each of the PK sample collection forms for the respective patients or a 
sample list should be included with each shipment. To prevent problems with 
illegible writing on tubes, consider numbering them (in addition to sample label) and 
numbering samples on the sample sheet.  
• Note the study number, PI, and the drugs used/to be measured.  
• A name, phone number, and email address should be included with samples so that 
receipt can be acknowledged.  
 
Shipping  
• All samples should be shipped via overnight express courier in insulated containers 
with enough dry ice to maintain the samples in a frozen state.  
• Tissue PK samples should be sent on Monday through Wednesday (never on 
Thursday. Friday, weekends, or days prior to a holiday) to: 
 
The OSUCCC Pharmacoanalytical Shared Resource 
Attn: Kasey Hill, PhD 
441 Biomedical Research Tower 
460 West 12th Avenue 
Columbus, Ohio 43210 
Phone: (614) 688-0578 
Fax: (614) 292-7766 
Email: PhASR@osumc.edu 
 
Upon shipment, send a notification with tracking number to the DFCI Coordinating 
Center at NeuroOnc_Coor@dfci.harvard.edu and OSUCCC Pharmacoanalytical 
Shared Resource at PhASR@osumc.edu 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
53 
 
Pharmacodynamic (PD), Tumor Microenvironment Samples, and Single-Cell RNA 
Sequencing Samples:  
Once local collection and analysis are complete, tissue samples for PD analysis [tubes 
labeled 2 (CE-PD), 4 (NCE-PD)] and single-cell RNA sequencing [tube labeled 6 (CE-
RNA)] as well as 10 slides from study surgery, and 20 slides from archived samples for 
PD and tumor multiplexed IF microenvironment analysis should be shipped to the central 
site (DFCI, Dr. Keith L. Ligon, JR McFaline-Figueroa, M Suva) within 30 days after 
surgery.  
 
• Email the DFCI Coordinating Center at NeuroOnc_Coor@dfci.harvard.edu at least 24 
hours prior to shipment of samples to confirm the receiving lab is aware of the shipment. 
• A memorandum indicating the study, the date of submission, name of study site 
submitting the tissue, and a list of contents. The DFCI Coordinating Center will supply a 
template memorandum to sites at the time of the SIV or upon request.  
• Include copy of the pathology and surgical reports for the sample being submitted 
 
Samples should be sent on a Monday through Thursday (never on Friday, weekends, or 
days prior to a holiday) to: 
 
Dr. Keith L. Ligon (attn.: Adult Path CRC) 
Dana-Farber Cancer Institute 
Center for Molecular Oncologic Pathology - JF215B 
450 Brookline Ave  
Boston, MA 02215 
Ph 617-632-2357 
 
Upon shipment, send a notification with tracking number to the DFCI Coordinating 
Center at NeuroOnc_Coor@dfci.harvard.edu 
 
Immunologic Samples:  
Samples for immunologic assays [fresh-preserved tumor tissue in tube labeled 5 (CE-
IM), FFPE slides from the protocol surgery, archival FFPE slides from prior surgery, and 
whole blood] should be shipped via FedEX for overnight delivery directly to UCLA. 
Guidelines for submission of these immunologic samples as follows (please see Table 9.2 
below for details): 
 
• FFPE slides from archival tissue and protocol surgery should be cut and 
submitted when requested by the DFCI Coordinating Center, when study 
recruitment has ended. Ship slides in a plastic slide holder/slide box. Place a 
small wad of padding in top of the container in order to avoid slides breaking 
during shipping and handling process.  
• Complete the provided UCLA Brain Tumor Research Lab memorandum 
indicating the study, subject ID assigned at registration, date of submission, name 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
54 
of study site submitting the tissue, and a list of contents. 
• The DFCI Neuro-Oncology Coordinating Center will provide supplemental 
Sample Collection & Shipping Guidance to sites at the time of activation or upon 
request.  
• Include a copy of the pathology and surgical report for the sample(s) being 
submitted.  
• Confirm the lab’s receiving availability by checking the web calendar. All 
samples should be shipped via FedEx for overnight delivery to UCLA. On-study 
tissue & blood samples should be obtained Sunday-Thursday for a Monday-
Friday arrival at UCLA.  UCLA is unable to accept samples on Saturday or 
Sundays.  
• An email is to be sent before each shipment to the UCLA Brain Tumor Research 
Lab at RPrinsLab@mednet.ucla.edu and the DFCI Coordinating Center at 
NeuroOnc_Coor@dfci.harvard.edu indicating what is being shipped and when.   
• Please note that the submitting institution is responsible for the costs of shipping 
and handling.  
• Ship samples to: 
Robert M. Prins, Ph.D. c/o Sylvia Odesa 
Gonda Research Lab, Room 1554 
695 Charles E. Young Drive South 
Los Angeles, CA 90095 
Telephone: 310-794-5663 
Email: RPrins@mednet.ucla.edu and SOdesa@mednet.ucla.edu  
 
Upon shipment, send a notification with tracking number to the DFCI Coordinating 
Center at NeuroOnc_Coor@dfci.harvard.edu and UCLA at RPrins@mednet.ucla.edu 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

 
 
 
55 
Table 9.2: Summary of Correlative Studies 
Biomarker name 
(Lead PI and Site) 
Cohort 
Assay 
Tissue/Body Fluid 
Tested 
and Timing of Assay 
Collection and Packaging 
Address to Send Sample  
Tissue PK 
(M. Phelps, OSU) 
Cohort 
1 
Liquid 
chromatography - 
tandem mass 
spectrometry (LC-
MS/MS) 
Fresh frozen tissue 
from protocol surgery 
(enhancing and non-
enhancing tumor) 
Protocol surgery: 200mg of fresh frozen tissue 
from the contrast-enhancing tumor placed into 
individual cryovial labeled 1 (CE-PK). If 
deemed medically safe and feasible, 200mg of 
fresh tissue from non-contrast-enhancing tumor 
and placed into individual cryovial labeled 3 
(NCE-PK). 
The OSUCCC Pharmacoanalytical Shared 
Resource 
Attn: Kasey Hill, PhD 
441 Biomedical Research Tower 
460 West 12th Avenue 
Columbus, Ohio 43210 
Phone: (614) 688-0578 
Fax: (614) 292-7766 
Email: PhASR@osumc.edu 
Plasma PK 
(M. Phelps, OSU) 
Cohort 
1 
Liquid 
chromatography - 
tandem mass 
spectrometry (LC-
MS/MS) 
Peripheral blood 
(pre-treatment, D8, at 
tumor resection) 
4mL blood should be collected (EDTA) prior to 
start of pre-surgery drug Day 1 (pre-dose), pre-
surgery Day 8 (pre-dose), and on day of surgery 
at time of tumor resection. 
 
Plasma should be separated and collected in a 
cryotube (polypropylene cryovials Nunc) that 
can be snap frozen. Plasma PK cryotubes should 
be labeled with date drawn, time drawn, 
participant number & initials, and PK time 
point, then frozen at -70°C or below 
The OSUCCC Pharmacoanalytical Shared 
Resource 
Attn: Kasey Hill, PhD 
441 Biomedical Research Tower 
460 West 12th Avenue 
Columbus, Ohio 43210 
Phone: (614) 688-0578 
Fax: (614) 292-7766 
Email: PhASR@osumc.edu 
Plasma PK 
(M. Phelps, OSU) 
Cohort 
2 
Liquid 
chromatography - 
tandem mass 
spectrometry (LC-
MS/MS) 
Peripheral blood 
4mL blood should be collected (EDTA) pre-
dose at C1D1, C2D1, C3D1 and C4D1. 
 
Plasma should be separated and collected in a 
cryotube (polypropylene cryovials Nunc) that 
can be snap frozen. Plasma PK cryotubes should 
be labeled with date drawn, time drawn, 
participant number & initials, and PK time 
point, then frozen at -70°C or below 
The OSUCCC Pharmacoanalytical Shared 
Resource 
Attn: Kasey Hill, PhD 
441 Biomedical Research Tower 
460 West 12th Avenue 
Columbus, Ohio 43210 
Phone: (614) 688-0578 
Fax: (614) 292-7766 
Email: PhASR@osumc.edu 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
56 
Tissue PD IHC, 
Proteomics, and 
Tumor 
microenvironment 
(K Ligon, DFCI; 
JR McFaline-
Figueroa, DFCI) 
Cohort 
1 
IHC for pRb 
(S807/811), 
proliferation, and 
apoptosis 
IF Multiplex for 
immune markers / 
antigen 
presentation  
Archived FFPE tissue 
and fresh frozen 
tissue from protocol 
surgery 
Archived: 20 unstained plus slides cut at 5um 
thickness 
Protocol surgery: 10 unstained slides cut at 5um 
thickness 
Protocol surgery: 200mg of fresh frozen tissue 
from the contrast-enhancing tumor placed into 
individual cryovial labeled 2 (CE-PD). If 
deemed medically safe and feasible, 200mg of 
fresh tissue from non-contrast-enhancing tumor 
and placed into individual cryovial labeled 4 
(NCE-PD). 
Dr. Keith L. Ligon (attn.: Adult Path CRC) 
Dana-Farber Cancer Institute 
Center for Molecular Oncologic Pathology - 
JF215B 
450 Brookline Ave  
Boston, MA 02215 
Phone 617-632-2357 
TIL Density and 
TCR Overlap  
(R Prins/T 
Cloughesy/ L Liau, 
UCLA) 
Cohort 
1 
TCR ImmunoSeq 
and TCR Overlap 
(Adaptive 
Biotech.) on 
tumor tissue and 
peripheral blood 
mononuclear cell 
genomic DNA 
Fresh preserved 
tissue from protocol 
surgery and 
peripheral blood (pre- 
and post-treatment) 
Protocol surgery: 200 mg of fresh tissue 
(approximately 20% tumor nuclei) sent in 2 mL 
Allprotect ® tissue reagent (Qiagen) or RNA-
later® reagent and placed into an individual 
cryovial labeled 5 (CE-IM). 
 
Pre-treatment and post-treatment PBMC can be 
used from blood collected for peripheral blood 
immunophenotyping (see below) 
Robert M. Prins, Ph.D. 
C/O Sylvia Odesa 
Gonda Research Lab, Room 1554 
695 Charles E. Young Drive South 
Los Angeles, CA 90095 
Phone: 310-794-5663 
Immunologic IHC 
measurements  
(R Prins/T 
Clougesy/L Liau, 
UCLA) 
Cohort 
1 
IF Multiplex for 
PD-1/PD-
L1/CD8/CD4/CD
8/CD6845/GFAP 
IHC on FFPE 
tumor tissue 
Archived FFPE tissue 
and protocol surgery 
FFPE tissue 
Slides are to be cut and submitted when 
requested by DFCI Coordinating Center. 
 
Archived: 7 FFPE unstained continuous 5 
micron thick slides on Superfrost Plus glass 
slides from most recent surgery revealing 
glioblastoma 
 
Protocol surgery: 7 FFPE unstained 
continuous 5 micron thick slides on 
Superfrost Plus glass slides 
Robert M. Prins, Ph.D. 
C/O Sylvia Odesa 
Gonda Research Lab, Room 1554 
695 Charles E. Young Drive South 
Los Angeles, CA 90095 
Phone: 310-794-5663 
Peripheral Blood 
Immunopheno-
typing 
(R Prins/ T 
Cloughesy/ L Liau, 
UCLA) 
Cohort 
1 
Mass Cytometry 
on peripheral 
blood 
mononuclear cells 
Peripheral blood 
(Pre-surgery pre-
treatment, pre-
surgery post -
treatment) 
Pre-surgery pre treatment blood: 10 Green top 
tubes (10ml/tube – sodium heparin tubes 
preferred) following registration/randomization 
and pre-abemaciclib 
 
Pre-surgery post treatment blood:10 Green top 
tubes (10ml – sodium heparin tubes preferred) 
prior to abemaciclib dosing on the morning of 
Robert M. Prins, Ph.D. 
C/O Sylvia Odesa 
Gonda Research Lab, Room 1554 
695 Charles E. Young Drive South 
Los Angeles, CA 90095 
Phone: 310-794-5663 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
57 
 
 
 
 
surgery 
Gene expression 
signatures and 
somatic mutations  
(R Prins / T 
Cloughesy / L 
Liau, UCLA) 
Cohort 
1 
RNA Seq on 
tumor 
gDNA/RNA 
Fresh preserved 
tissue from protocol 
surgery and 
peripheral blood (pre- 
and post-treatment) 
The protocol surgery sample labeled 5 (CE-IM). 
collected for TIL Density and TCR Overlap will 
also be used for gene expression signatures and 
somatic mutations.  
 
Pre-treatment and post-treatment PBMC can be 
used from blood collected for peripheral blood 
immunophenotyping (see above). 
Robert M. Prins, Ph.D. 
C/O Sylvia Odesa 
Gonda Research Lab, Room 1554 
695 Charles E. Young Drive South 
Los Angeles, CA 90095 
Phone: 310-794-5663 
Single-cell RNA-
sequencing (M 
Suva, MGH) 
Cohort 
1 
Single-cell RNA-
sequencing 
(SMART-Seq2) 
Frozen tissue from 
protocol surgery 
Protocol surgery: 200mg of fresh frozen tissue 
(frozen on dry ice, no OCT, no LN2) < 3 hours 
from surgery, obtained from the contrast 
enhancing region and placed into an individual 
cryovial labeled 6 (CE-RNA).Freeze the tumor 
specimen (frozen on dry ice, no OCT, no LN2). 
200 mg (~0.5cm3) of tissue. 
Dr. Keith L. Ligon (attn.: Adult Path CRC) 
Dana-Farber Cancer Institute 
Center for Molecular Oncologic Pathology - 
JF215B 
450 Brookline Ave  
Boston, MA 02215 
Phone 617-632-2357 
Cell line studies  
(K Ligon, DFCI) 
Cohort 
1 
Dynamic response 
to abemaciclib in 
vitro 
Cell line derived 
from protocol surgery 
Protocol surgery: 200mg or more tissue should 
be sent fresh to the local hospital research lab 
for establishment of a participant primary cell 
line (serum free, neurosphere methods) by the 
site’s standard procedures.  For sites that create 
cell lines locally the central site (DFCI, Dr. 
Keith L. Ligon) will request frozen aliquot of 
live cells in DMSO – if available – at a later date 
(may be ~ 6 months after surgery); but this is not 
a mandated study submission.  
 
If the local site does not have capability or 
would prefer the fresh tissue can be submitted in 
RMPI media to Dr. Ligon’s lab for culture 
instead of the local site.  This should be shipped 
at 4 degrees on wet ice.   
Dr. Keith L. Ligon (attn.: Adult Path CRC) 
Dana-Farber Cancer Institute 
Center for Molecular Oncologic Pathology - 
JF215B 
450 Brookline Ave  
Boston, MA 02215 
Ph 617-632-2357 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

 
 
 
58 
Cohort 1 Blood Samples for Peripheral Blood Immunophenotyping: 
 
Ten Green top tubes (each 10ml/tube – sodium heparin tubes preferred) should be 
collected prior to the start of pre-surgery Day 1 (pre-dose) and prior to morning 
abemaciclib dose on day of surgery. Blood samples for immunologic assays should be 
shipped (along with the fresh-preserved tumor tissue) via FedEX for overnight delivery 
directly to UCLA as described in Table 9.2. 
 
Cohorts 1 & 2 Plasma Pharmacokinetic (PK) Samples: 
 
Cohort 1 Pre-Surgery/Surgery 
4mL blood should be collected in purple-top EDTA vacutainer (Becton Dickinson Catalog 
# 367861 or 367844, Franklin Lakes, NJ) prior to start of pre-surgery Day 1 (pre-dose), 
pre-surgery Day 8 (pre-dose), and on day of surgery at time of tumor resection.  All 
samples should be prior to morning abemaciclib dose. 
 
Cohort 2 
For all Cohort 2 participants, 4mL blood should be collected (in purple-top EDTA 
vacutainer (Becton Dickinson Catalog # 367861 or 367844, Franklin Lakes, NJ) at C1D1 
(pre-treatment), C2D1, C3D1 and C4D1(if a participant comes off study treatment prior to 
C4D1 visit, then an end of treatment sample should be drawn). All samples should be prior 
to morning abemaciclib dose. 
Handling of Specimen(s) 
• Obtain venous blood by standard phlebotomy technique from a peripheral access 
point.  NOTE:  Suggest using a minimum 18G needle to avoid sample hemolysis.   
• Fill-up the tubes as much as possible until blood flow stops. 
• GENTLY invert each tube several times (8-10 times) immediately after collection to 
avoid sample hemolysis. 
• Place samples immediately on ice after collection; samples must be processed within 
20 minutes. 
 
Processing instructions 
1. Invert sample 8-10 times immediately before processing.   
2. Place the sample(s) on ice or in a refrigerator and separate the plasma within 60 
minutes of collection at 1,500 - 2,000 x g for 10 minutes in swinging bucket (SW) or 
15 minutes in a fixed angel (FA) rotor at 4ºC in a refrigerated centrifuge.  Make sure 
that the centrifuge reaches speed and is maintained throughout the entire spin. 
3. Carefully remove tube from centrifuge.  
4. Using a pipette, transfer equal aliquots of plasma into 2 labeled 2 mL cryovials, not 
exceeding 1.5 mL per cryovial.   
5. Label samples as Abemaciclib PK, including protocol number (16-383), unique 
patient ID (assigned by the consortium), initials, date of collection, draw time, and 
time point. 
6. Store plasma samples at -70oC or below until shipment or transfer to OSU. 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
59 
Plasma PKs will be batch shipped when requested by the DFCI Coordinating Center. 
 
Preparing the shipment 
E-mail the DFCI Coordinating Center at NeuroOnc_Coor@dfci.harvard.edu at least 24 
hours prior to shipment of samples to confirm the receiving lab is aware of the shipment.  
 
Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH).  
• Organize the samples by patient and timepoint in the box.  
• Do not store in plastic bags (they break on dry-ice and labels will detach).  
• A copy of each of the PK sample collection forms for the respective patients or a 
sample list should be included with each shipment. To prevent problems with 
illegible writing on tubes, consider numbering them (in addition to sample label) and 
numbering samples on the sample sheet.  
• Note the study number, PI, and the drugs used/to be measured.  
• A name, phone number, and email address should be included with samples so that 
receipt can be acknowledged.  
 
Shipping  
• All samples should be shipped via overnight express courier in insulated containers 
with enough dry ice to maintain the samples in a frozen state.  
• Tissue PK samples should be sent on Monday through Wednesday (never on 
Thursday. Friday, weekends, or days prior to a holiday) to: 
 
The OSUCCC Pharmacoanalytical Shared Resource 
Attn: Kasey Hill, PhD 
441 Biomedical Research Tower 
460 West 12th Avenue 
Columbus, Ohio 43210 
Phone: (614) 688-0578 
Fax: (614) 292-7766 
Email: PhASR@osumc.edu 
 
Upon shipment, send a notification with tracking number to the DFCI Coordinating Center 
at NeuroOnc_Coor@dfci.harvard.edu and the OSUCCC Pharmacoanalytical Shared 
Resource at PhASR@osumc.edu 
 
Archival Tissue Samples for Screening and Correlative Studies 
 
Guidelines for submission of archival tumor tissue and for PD and tumor antigen presentation 
and microenvironment correlative studies at DFCI: 
• A memorandum indicating the study, the date of submission, name of study site 
submitting the tissue, and a list of contents. The DFCI Coordinating Center will supply a 
template memorandum to sites at the time of the SIV or upon request. 
• Include copy of the pathology, surgical, and genomic profiling/sequencing reports for the 
sample being submitted  
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
60 
• Email the DFCI Coordinating Center at NeuroOnc_Coor@dfci.harvard.edu at least 24 
hours prior to shipment of samples to confirm the receiving lab is aware of the shipment.  
 
Samples should be sent on a Monday through Thursday (never on Friday, weekends, or 
days prior to a holiday) to: 
 
Dr. Keith L. Ligon (attn.: Adult Path CRC) 
Dana-Farber Cancer Institute 
Center for Molecular Oncologic Pathology - JF215B 
450 Brookline Ave  
Boston, MA 02215 
Ph 617-632-2357 
 
Upon shipment, send a notification with tracking number to the DFCI Coordinating 
Center at NeuroOnc_Coor@dfci.harvard.edu 
 
Guidelines for submission of archival tumor tissue for immunologic correlative studies at UCLA:  
• FFPE slides from archival tissue should be cut and submitted when requested by the 
DFCI Coordinating Center, when study recruitment has ended. Ship slides in a plastic 
slide holder/slide box. Place a small wad of padding in top of the container in order to 
avoid slides breaking during shipping and handling process. 
• Complete the provided UCLA Brain Tumor Research Lab memorandum indicating the 
study, subject ID assigned at registration, date of submission, name of study site 
submitting the tissue, and a list of contents. 
• The DFCI Neuro-Oncology Coordinating Center will provide supplemental Sample 
Collection & Shipping Guidance to sites at the time of activation or upon request.   
• Include a copy of the pathology and surgical report for the sample being submitted  
• An email is to be sent before each shipment to the UCLA Brain Tumor Research Lab at 
RPrinsLab@mednet.ucla.edu and the DFCI Coordinating Center at 
NeuroOnc_Coor@dfci.harvard.edu indicating what is being shipped and when.   
• Please note that the submitting institution is responsible for the costs of shipping and 
handling.  
• Ship slides to: 
Robert M. Prins, Ph.D. 
C/O Sylvia Odesa 
Gonda Research Lab, Room 1554 
695 Charles E. Young Drive South 
Los Angeles, CA 90095 
Telephone: 310-794-5663 
Email: RPrins@mednet.ucla.edu and SOdesa@mednet.ucla.edu  
 
Upon shipment, send a notification with tracking number to the DFCI Coordinating 
Center at NeuroOnc_Coor@dfci.harvard.edu and UCLA at RPrins@mednet.ucla.edu 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
61 
9.2.1 DFCI/BWH Testing of Pre-Post Treatment Tumor Tissue 
 
An example of the DFCI prescreening results that may be generated prior to trial entry is 
described below. In addition, all Cohort 1 on surgery samples will be tested post-treatment tissue 
using these same assays for comparison to pre-treatment tissue. DFCI FFPE tumor tissue from 
the participant’s surgery prior to enrolling onto the study or Cohort 1 post-treatment tissue will 
be genotyped with the clinically validated OncoPanel targeted exome sequencing for 300 cancer 
causing genes and whole genome OncoCopy Agilent array comparative genomic hybridization at 
1M probe resolution, and the results correlated with outcome. Both assays are performed in the 
CLIA-certified laboratory at the Dana-Farber/Brigham and Women’s Cancer Center, Center for 
Advanced Molecular Diagnostics (CAMD).  
 
9.2.1.1 
OncoCopy Whole Genome Array CGH (DFCI/BWH) 
 
Tissue requirements for aCGH are 10 x 5 μm standard formalin-fixed paraffin embedded (FFPE) 
tumor sections or 5 x 0.5 mm tissue cores containing at least 50% tumor nuclei and less than 
10% necrosis. At least 1.3 u μg tumor DNA (nanodrop quantification) is required.  As previously 
described, aCGH is performed using DNA fragmentation simulation methods (FSM) with 
Agilent SurePrint G3 1x1M arrays (Craig et al., 2012).  Whole genome data are generated and 
analyzed using proprietary cytogenomics software. Copy number aberrations (CNAs) are curated 
to prioritize genetic events most likely to have diagnostic, prognostic and/or therapeutic 
significance in brain tumors in order to generate a genotyping list of at least 40 different genomic 
imbalances.  The time required from tissue submission to data reporting averages two weeks or 
less.  A distinct advantage of this assay is that whole genome data may be reanalyzed at later 
time points or in exploratory arms of the study without additional cost. In addition, the use of a 
dedicated and robust copy number assay whose performance is well characterized allows for 
inclusion of more reproducible results in future studies.  
 
9.2.2 OncoPanel Targeted Exome Sequencing (DFCI/BWH) 
 
DNA will be isolated from 5-10 5 μm FFPE slides or 3 x 0.6 mm tissue cores, frozen tissue or 
genomic DNA from a CLIA lab containing at least 50% tumor nuclei using routine extraction 
methods previously described (Wagle et al., 2012). At least 200ng of genomic dsDNA is 
required (PicoGreen quantification).  Somatic mutations in tumor DNA will be detected using 
the high-throughput targeted deep sequencing OncoPanel in the DF/BWCC CLIA-certified 
laboratory at the Brigham and Women’s Hospital (Center for Advanced Molecular Diagnostics- 
CAMD, Molecular Pathology Dr. Neal Lindeman, Director). Briefly, massively parallel 
sequencing libraries (Illumina) that contain barcoded universal primers will be generated using 
genomic DNA from FFPE tumor material to be used in solution-phase hybrid capture with 
biotinylated RNA baits. Sequencing data is analyzed for single nucleotide sequence variants, 
small insertions/deletions, and DNA copy-number alterations in exons from 275 actionable 
cancer genes including oncogenes and tumor suppressors. 
 
9.2.3 Immunohistochemistry Correlates for Cohort 1 Patients 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
62 
Tumor from all patients will be evaluated by IHC for PD (including the levels of pRB1, CC3, 
Ki67, and other markers of abemaciclib), tumor microenvironment, as well as immunologic 
changes in pre or pre-post treatment pairs. These studies will require a total of 17 IHC unstained 
plus slides cut at 5um thickness (Cohort 1 and 2, archived and study surgery). Ten slides should 
be sent to Dr. Keith Ligon at DFCI and 7 slides (on Superfrost Plus glass slides) should be sent 
to Dr. Robert Prins at UCLA. This is for correlation only and is not utilized for trial 
entry/screening. 
 
9.3 
Special Studies 
 
Cell Line Sample:  
 
Primary glioblastoma patient derived cell lines (PDCLs) derived from glioblastoma participants 
have been shown to retain key genetic and expression characteristics of the parent tumor and 
offer a potentially advantageous exploratory mechanism for biologic analysis of response in 
individual participant tumors as well as potential diagnostic predictor of participant response to 
drug. Primary glioblastoma cell lines develop successfully from roughly half of all attempts at 
culturing. Attempted culturing of PDCLs is expected for all Cohort I surgeries. In addition, for 
participants who are also enrolled in the Ivy Stage 0 tissue banking protocol, cells lines 
established at new diagnosis may be available. As such we will seek to study and compare 
responses to abemaciclib in any participant cell lines which are derived by participating sites 
from newly diagnosed or treated participant specimens at recurrence. Cell lines will be studied 
for the dynamic response to abemaciclib in vitro as read out by similar IHC, Western, and 
pharmacodynamic measures described for tissue samples above (e.g., pRb reduction, KI-67 
measurement of proliferation index). These studies will be coordinated or performed by the 
laboratory of Dr. Keith Ligon at DFCI.  
 
To achieve a cell line, an additional sample (200mg size of green pea or larger) should be sent 
fresh to the local hospital research lab for establishment of a participant primary cell line (serum 
free, neurosphere methods) by the site’s standard procedures. If the local site does not have 
capability or would prefer the fresh tissue can be submitted in RMPI media to Dr. Ligon’s lab for 
culture instead of the local site.  This should be shipped at 4 degrees on wet ice.  All cell lines 
derived from the study participants will be shared with the site of referral.  For sites that create 
cell lines locally the central site (DFCI, Dr. Keith L. Ligon) will request frozen aliquot of live 
cells in DMSO – if available – at a later date (may be ~ 6 months after surgery); but this is not a 
mandated study submission.  
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
63 
10. STUDY CALENDAR 
 
Table 10 describes required procedures. All procedures may increase in frequency if clinically 
indicated or oriented following a toxicity/adverse event.  
Table 10.1 Required Activity Calendar for Cohort 1 only 
 
 
Examination 
Screening
a 
Pre-Surgery 
During 
Surgery
d 
Post-
Surgery
e 
30-Day Post 
Drug
f 
D1
b 
D8
c 
Informed consent
g 
X 
 
 
 
 
 
Background Information 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria
h 
X 
 
 
 
 
 
Serum Pregnancy Test
i  
X 
X 
 
 
 
 
Vital Signs
j 
X 
 
 
 
 
 
Neuro & Physical Exam 
X 
 
 
 
 
 
KPS 
k 
X 
 
 
 
 
X 
Con-Med & Adverse Event 
Assessments l 
 
--------------------------------X-------------------------------- 
12-lead ECG  
X 
 
 
 
 
 
Imaging – MRI 
m 
X 
 
 
 
 
 
Hematology n 
X 
X 
X 
 
 
 
Serum Chemistry 
o 
X 
X 
X 
 
 
 
Coagulation (PT/INR, PT, PTT) 
X 
 
 
 
 
 
Submission of Archival Tissue
p 
X 
 
 
 
 
 
Blood for Immunophenotyping q 
 
X 
 
X 
 
 
Plasma PK Collection r 
 
X 
X 
X 
 
 
Tumor Resection s 
 
 
 
X 
 
 
Abemaciclib Administration t 
 
Every 12 hours including 
morning of surgery 
none 
 
a. To be performed within 14 days of registration unless specified otherwise.  
b. Pre-surgery Day 1 assessments to be performed within 3 days prior to drug day 1 unless specified 
otherwise.   
c. 
Pre-surgery Day 8 assessments to be performed within +/- 1 day. 
d. Surgery to occur after participant is on daily drug for 10-14 days.  Abemaciclib is to be taken on the 
morning of/before the surgery 1-3 hours prior to surgery and tumor removal.  Since participants in 
cohort 1 are undergoing PK testing, accurately regarding the time of study drug administration on day of 
surgery and recording the time of tumor removal are especially required. Procedures to be documented 
during surgery, and samples to be collected, are detailed in section 9.    
e. Post-surgery period is the time following surgery.  No protocol specific assessments are required for this 
period; sites may obtain assessments as clinically indicated.  
f. 
A contact/visit for review of concomitant medications, adverse events, and KPS (no neurologic exam 
required at 30-day FU time point) is to be performed at 30 days + 7 days after the last study drug is 
given. This may be performed via documented phone conversation with a study nurse or clinician. All 
participants will be followed until resolution or stabilization of any serious adverse events occurring 
during treatment or starting within 30 days of last study drug 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
64 
 
 
 
g. Per DF/HCC multi-center policy, must be obtained by MD attending. Informed Consent may be performed up to 
28 days prior to registration Per DF/HCC multi-center policy, must be obtained by MD attending. Informed 
Consent may be performed up to 28 days prior to registration. 
h. Please see section 3. Genomic profiling data from previously performed sequencing and/or copy number array 
data to verify status of CDKN2A/B/C and RB1 must be available prior to registration.  
i. 
Serum pregnancy test only for women of child bearing potential (as defined in Section 3.1.20). Serum pregnancy 
test within 7 days prior to Day 1 drug for registration purposes and repeated within 72 hours prior to Day 1 drug 
if original screening pregnancy test is not within 72 hours of Day 1 drug. 
j. 
Vital signs:  Weight, heart rate, blood pressure, respiration rate, temp.  Height required only at baseline (any 
height within 1 year of registration is acceptable). 
k. 
Karnofsky Performance Status (KPS)  
l. 
Adverse events experienced by participants will be collected and reported from initiation of study medication, 
throughout the study, and within 30 days of the last dose of study medication. Participants who experience an 
ongoing adverse event related to a study procedure and/or study medication beyond 30 days will continue to 
be contacted by a member of the study team until the event is resolved, stabilized, or determined to be 
irreversible by the participating investigator.  Concomitant medications and reason for administration should be 
documented in the case history from date of consent up to the 30-Day Post Drug Visit. 
m. Imaging: gadolinium-enhanced contrast and non-contrast MRI.  CT alternative, if MRI contraindicated.  When 
feasible at a site, appendix G MRI Acquisition Protocol should be adhered to.Imaging: gadolinium-enhanced 
contrast and non-contrast MRI.  CT alternative, if MRI contraindicated.  When feasible at a site, appendix G MRI 
Acquisition Protocol should be adhered to and the same imaging technique should be used in a participant 
throughout the trial. Screening baseline scan within 14 days prior to registration. 
n. Hematology – erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils)Hematology – erythrocytes (RBC), hemoglobin, hematocrit, 
platelets, total WBC plus differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils).  
o. Biochemistry - albumin, alkaline phosphatase (ALP), bicarbonate (HCO3), BUN, calcium, chloride, creatinine, 
glucose, magnesium, phosphorous, potassium, SGOT (AST), SGPT (ALT), sodium, total protein, total bilirubin, 
amylase and lipase, LDH and uric acid.  If total bilirubin is greater than the upper limit of normal, direct and 
indirect bilirubin should be performed.  
Coagulation assays of PT/INR, PT, PTT required at screening only.   
p. Archival tumor tissue per eligibility point 3.1.11 must be submitted to the DFCI Coordinating Center within 60 
days of registration. 
q. Required at pre surgery C1D1 (pre-dose) and prior to the morning dose on the day of surgery.  
r. 
Required at pre surgery C1D1 (pre-dose), pre-surgery Day 8 (pre-dose), and day of surgery at the time of tumor 
resection for Cohort 1 participants. 
s. 
See section 9 for details on tumor tissue requirements. On-study surgery tissue should be submitted within 60 
days of date of surgery. 
t. 
Please see protocol section 8.1.8 for abemaciclib administration instructions    
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
65 
Table 10.2 Required Activity Calendar for Cohort 2 only 
 
 
Examination 
Screeninga 
Cycle 1 
Subsequent 
Cycles 
End of 
Txe 
30-day post 
drugf 
Long Term 
Follow Upg 
D1b 
D15c 
D1d 
Informed Consenth 
X 
 
 
 
 
 
 
Background Information 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteriai 
X 
 
 
 
 
 
 
Serum Pregnancy Testj  
X 
X 
 
X 
 
 
 
Vital Signsk 
X 
X 
X 
X 
X 
 
 
Neuro & Physical Exam 
X 
X 
X 
X 
X 
 
 
KPSl 
X 
X 
X 
X 
X 
X 
 
Con-Med & Adverse Event 
Assessmentsm 
 
------------------------------X---------------------------- 
 
12-lead ECG  
Xn 
 
 
Xn 
 
 
 
Imaging – MRIo 
Xp 
Xp 
 
Xo 
X 
 
 
Response Assessmentq 
 
 
 
X 
X 
 
 
Hematologyr 
X 
X 
X 
X 
X 
 
 
Serum Chemistrys 
X 
X 
X 
X 
X 
 
 
Coagulation (PT/INR, PT, PTT) 
X 
 
 
 
 
 
 
Submission of Archival Tissue 
X t 
 
 
 
 
 
Xw  
Plasma PK Collectionu 
 
X 
 
X 
 
 
 
Abemaciclib Administrationv 
 
Every 12 
hours 
Every 12 hours 
 
 
 
Follow-Up Info 
 
 
 
 
 
X 
a. 
To be performed within 14 days of registration unless specified otherwise.  
b. To be performed within 3 days prior to drug day 1 unless specified otherwise.   
c. 
Cycle 1, Day 15 visit has a +/- 2 days window. 
d. Within 3 days prior to day 1 drug, except imaging which is within 7 days prior to day 1 drug. Results of all 
assessments (aside from correlative studies) must be reviewed prior to taking drug for respective cycle. 
e. End of treatment assessments to be performed within +/- 7 days of last study drug or within +/- 7 days of 
decision to end treatment.  All participants will be followed until resolution or stabilization of any serious 
adverse events occurring during treatment or starting within 30 days of last study drug. 
f. 
A contact/visit for review of concomitant medications, adverse events, and KPS (no neurologic exam 
required at 30-day FU time point) is to be performed at 30 days +7 days after the last study drug is given.  
This may be performed via documented phone conversation with a study nurse or clinician. All participants 
will be followed until resolution or stabilization of any serious adverse events occurring during treatment 
or starting within 30 days of last study drug. 
g. Participants will be followed via medical record review until death for post-treatment therapies, 
progression information, and survival. Updates to the CRFs are to be made roughly every three months (+/- 
1 month). Each site will be responsible for collecting information on their participants regarding all post-
treatment therapies, start and stop dates of those therapies, the reason for stopping those therapies, and 
the date of death.    
h. Per DF/HCC multi-center policy, must be obtained by MD attending. Informed Consent may be performed 
up to 28 days prior to registration.    
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
66 
 
 
 
i. 
Please see section 3. Genomic profiling data from previously performed sequencing and/or copy number 
array data to verify status of CDKN2A/B/C and RB1 must be available prior to registration.  
j. 
Serum pregnancy test only for women of child bearing potential (as defined in Section 3.1.20). Serum 
pregnancy test within 7 days prior to Day 1 drug for registration purposes and repeated within 72 hours prior 
to Day 1 drug if original screening pregnancy test is not within 72 hours of Day 1 drug. 
k. 
Vital signs:  Weight, heart rate, blood pressure, respiration rate, temp.  Height required only at baseline (any 
height within 1 year of registration is acceptable). 
l. 
Karnofsky Performance Status (KPS)  
m. Adverse events experienced by participants will be collected and reported from initiation of study medication, 
throughout the study, and within 30 days of the last dose of study medication. Participants who experience 
an ongoing adverse event related to a study procedure and/or study medication beyond 30 days will continue 
to be contacted by a member of the study team until the event is resolved, stabilized, or determined to be 
irreversible by the participating investigator.  Concomitant medications and reason for administration should 
be documented in the case history from date of consent up to the 30-Day Post Drug Visit. 
n. EKG at screening and C2D1 only.  
o. Imaging: gadolinium-enhanced contrast and non-contrast MRI.  CT alternative, if MRI contraindicated.  When 
feasible at a site, appendix G MRI Acquisition Protocol should be adhered to and the same imaging technique 
should be used in a participant throughout the trial. Imaging to be done at all odd cycles (C3D1, C5D1, etc.).  
p. Within 14 days prior to registration (screening baseline scan). For the scan prior to treatment cycle 1 day 1, if 
steroids are added or increased between the date of the scan and the start of treatment, new baseline 
imaging is required.  
q. Response assessment using RANO criteria, at time of imaging and as indicated clinically. 
r. 
Hematology – erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils).  
s. 
Biochemistry - albumin, alkaline phosphatase (ALP), bicarbonate (HCO3), BUN, calcium, chloride, creatinine, 
glucose, magnesium, phosphorous, potassium, SGOT (AST), SGPT (ALT), sodium, total protein, total bilirubin, 
amylase and lipase, LDH and uric acid.  If total bilirubin is greater than the upper limit of normal, direct and 
indirect bilirubin should be performed.  
t. 
Archival tumor tissue per eligibility point 3.1.11 must be submitted to the DFCI Coordinating Center within 60 
days of registration Archival tumor tissue per eligibility point 3.1.11 must be submitted to the DFCI 
Coordinating Center within 60 days of registration. 
u. Required at C1D1 (pre-dose), C2D1, C3D1 and C4D1 for Cohort 2 participants.  If a participant comes off study 
treatment prior to C4D1 then an end of treatment PK sample should be drawn. See section 9 for details on PK 
timing and processing requirements. 
v. 
Please see protocol section 8.1.8 for abemaciclib administration instructions. 
w. Tissue from subsequent surgery or post-mortem exam:  In the event that the participant undergoes any 
subsequent surgery for tumor resection, if possible, tumor tissue will be acquired to evaluate potential 
mechanisms of resistance to therapy with abemaciclib. Dr. Keith Ligon should be consulted for specifications 
prior to surgery when possible. 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
67 
11. MEASUREMENT OF EFFECT 
 
This trial will utilize the criteria recently proposed by the Response Assessment in Neuro-
Oncology (RANO) working group (Wen et al., 2010). 
 
Radiologic assessment will be determined by the Response Assessment in Neuro-Oncology 
Working Group (RANO) Criteria using bidirectional tumor measurements with some 
modifications. In addition to imaging characteristics, these criteria include consideration of 
neurological function and corticosteroid use (Wen et al., 2010). The RANO Criteria is outlined in 
detail in this section. 
 
Magnetic resonance imaging (MRI) is the most readily available and reproducible method of 
disease assessment and is required for this study. The largest and most representative lesions 
should be measured either on axial, coronal or sagittal slices, and chosen to be followed for 
response evaluation. 
 
The recommended sequences are outlined in detail in Appendix G and should conform as closely 
as possible to the consensus recommendations for a standardized Brain Tumor Imaging Protocol 
in clinical trials. 
 
11.1 
Antitumor Effect – Definitions 
 
Evaluable for toxicity. All participants who receive at least one dose of study treatment 
will be evaluable for toxicity from the time of their first treatment. 
 
Evaluable for objective response. Only those participants who have measurable disease 
present at baseline (cycle 1, day 1 scan) and have received at least one dose of therapy will 
be considered evaluable for response. These participants will have their response classified 
according to the definitions stated below. (Note: Participants who exhibit objective disease 
progression or die prior to the end of cycle 1 will also be considered evaluable.) 
 
Measurable disease. Bidimensionally, contrast-enhancing, measurable lesions with clearly 
defined margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 
axial slices which are at least 5 mm apart with 0 mm skip. Measurement of tumor around a 
cyst or surgical cavity, if necessary, requires a minimum thickness of 3 mm. If there are 
too many measurable lesions to measure at each evaluation, the investigator must choose 
the largest two to be followed before a participant is entered on study.  The remaining 
lesions will be considered non-measureable for the purpose of objective response 
determination.  Unless progression is observed, objective response can only be determined 
when all measurable and non-measurable lesions are assessed. 
 
Non-measurable evaluable disease. Unidimensionally measurable lesions, masses with 
margins not clearly defined, lesions with maximal diameter < 1cm.  
 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
68 
11.2 
Response/Progression Categories 
 
Complete response (CR). All of the following criteria must be met:   
a) Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks.  In the absence of a confirming scan 4 weeks later, 
this scan will be considered only stable disease. 
b) No new lesions. 
c) All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
d) Participants must be on no steroids or on physiologic replacement doses only. 
e) Stable or improved non-enhancing (T2/FLAIR) lesions  
f) Stable or improved clinically, for clinical signs and symptoms present at baseline 
and recorded to be disease related 
 
Participants with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 
 
Partial response (PR).  All of the following criteria must be met: 
a) Greater than or equal to 50% decrease compared to baseline in the sum of products 
of perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan will be 
considered only stable disease.  
b) No progression of non-measurable disease. 
c) No new lesions.  
d) All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline.  
e) The steroid dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan. 
f) Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
g) Stable or improved, for clinical signs and symptoms present at baseline and 
recorded to be disease related clinically. 
 
 
Participants with non-measurable disease cannot have a partial response. The best 
response possible is stable disease. 
 
Progressive disease (PD). The following criterion must be met: 
a) > 25% increase in sum of the products of perpendicular diameters of enhancing 
lesions (over best response or baseline if no decrease) on stable or increasing doses 
of corticosteroids 
and/or one or more of the of the following: 
b) Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing 
doses of corticosteroids steroids compared to baseline scan or best response 
following initiation of therapy, not due to co-morbid events (radiation therapy, 
demyelination, ischemic injury, infection, seizures, post-operative changes, or other 
treatment effects). 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
69 
c) Any new lesion 
d) Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g. seizures, medication side effects, complications of therapy, cerebrovascular 
events, infection, etc.). The definition of clinical deterioration is left to the 
discretion of the investigator but it is recommended that a decline in the Karnofsky 
Performance Score (KPS) from 100 or 90 to 70 or less, a decline in KPS of at least 
20 from 80 or less, or a decline in KPS from any baseline to 50 or less, for at least 7 
days, be considered neurologic deterioration, unless attributable to co-morbid 
events or changes in corticosteroid dose. 
e) Failure to return for evaluation due to death or deteriorating condition 
 
Stable disease (SD). All of the following criteria must be met: 
a) Does not qualify for CR, PR, or progression. 
b) All measurable and non-measurable sites must be assessed using the same 
techniques as baseline. 
c) Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose has been 
increased, the last scan considered to show stable disease will be the scan obtained 
when the corticosteroid dose was equivalent to the baseline dose. 
d) Stable clinically. 
 
Unknown response status. Progressive disease has not been documented and one or more 
measurable or non-measurable lesions have not been assessed. 
 
These RANO Response Criteria are also summarized in the following table: 
 
Table 10.2: Summary of the RANO Response Criteria 
 
CR 
PR 
SD 
PD# 
T1-Gd + 
None 
≥50% decrease 
<50% decrease- 
<25% increase 
≥25% increase* 
T2/FLAIR 
Stable or 
decrease 
Stable or 
decrease 
Stable or 
decrease 
Increase* 
New Lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or 
decrease 
Stable or 
decrease 
NA 
Clinical Status 
Stable or 
increase 
Stable or 
increase 
Stable or increase 
Decrease* 
Requirement for 
Response  
All 
All 
All 
Any* 
CR=complete response;   PR=partial response;   SD=stable disease;   PD=progressive disease 
#:    Progression occurs when any of the criteria with * is present 
NA: Increase in corticosteroids alone will not be taken into account in determining progression 
in the absence of persistent clinical deterioration 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
70 
11.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool. All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 14 days from the date of registration. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
 
11.4 
Evaluation of Best Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). If a response recorded at one scheduled MRI does not 
persist at the next regular scheduled MRI, the response will still be recorded based on the prior 
scan, but will be designated as a non-sustained response.  If the response is sustained, i.e. still 
present on the subsequent MRI, it will be recorded as a sustained response, lasting until the time 
of tumor progression. Participants without measurable disease may only achieve SD or PD as 
their best “response.” 
 
11.5 
Other Effect Measures 
 
Neurological Exam 
Although not used for determining response, it is useful to evaluate changes in the neurological 
exam compared to the previous exam.  The following scale may be used:  
 
+2  
Definitely better 
+1  
Possibly better 
  0 
Unchanged 
- 1  
Possibly worse 
- 2  
Definitely worse 
 
Performance Status:  
Participants will be graded according to KPS score  
 
Overall survival time:  
From date of first dose (date of first post surgery treatment for participants in Cohort 1) to 
date of death due to any cause. 
  
Progression-free survival time:  
From date of first dose (date of first post surgery treatment for participants in Cohort 1) to 
date of progression or death. Participants who stop treatment for causes other than 
progression may be censored if other therapy is initiated or if regular assessments for 
assessing progression are no longer available. 
 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
71 
11.6 
Response Review at DFCI Coordinating Center 
 
Central review of MRI or CT scans is planned for participants who achieve CR, PR, or PFS6.   
 
Central review will be performed by Dr. Lee or her designee for registered subjects who have 
been determined by the enrolling institution as having achieved PFS6, complete radiographic 
response, or partial radiographic response. When a participant’s films are requested by the DFCI 
Coordinating Center and Overall PI, all films of all views from pre-registration and subsequent 
scans must be submitted for central review. Once the Central Review is complete, the central 
review results can be made available to the local PI.   
 
When imaging studies are requested by the Coordinating Center: 
• All films of all views from pre-registration and subsequent scans must be 
submitted for central review. 
• Transfer images to compact disc, labeled with study/case number and de-
identified per institution’s local policy.   
• A copy of all scan reports must be attached for inclusion in the submission.  
• A memo detailing what is being submitted should be included with submission (a 
template memo will be provided by the DFCI Coordinating Center) 
• Ship to: 
Eudocia Quant Lee, MD c/o Kristen Fisher 
Center for Neuro-Oncology 
Dana-Farber Cancer Institute 
450 Brookline Avenue, LG1B12A 
Boston, MA  02215 
Telephone: 617-632-4341 
 
The submitting institution is responsible for the costs of shipping and handling. 
 
 
 
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12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ. 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with ODQ 
On Study Form 
Within 30 days of registration 
Baseline Assessment Form 
Within 30 days of registration 
Treatment Form 
Within 14 days of treatment administration 
Adverse Event Report Form 
Within 14 days of AE assessment/notification 
Response Assessment Form 
Within 14 days of the response assessment 
Off Treatment/Off Study Form Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
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days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
12.3 
Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix B. 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 
• Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
 
This will be an open label Phase II trial in participants with recurrent GBM. Cohort 1 and Cohort 
2 will enroll concurrently. In Cohort 1, to ensure that adequate abemaciclib penetrates into the 
tumors and inhibits cellular proliferation, 15 participants with recurrent GBM who require 
reoperation will be treated with abemaciclib prior to surgery. After recovery from surgery, 
participants will receive abemaciclib until disease progression or the development of 
unacceptable toxicities. In Cohort 2, participants will receive abemaciclib without undergoing 
prior surgery. The two cohorts will be analyzed separately. 
 
In Cohort 1 we will attempt to characterize the pharmacokinetic (PK) uptake of abemaciclib in 
brain. A single-time point brain-to-plasma ratio will be calculated for each participant with a 
paired plasma and brain sample, followed by a descriptive statistical analysis (mean, SD, CV% 
or median (range)). In addition, both a naive pool strategy of all brain samples as well as a non-
linear mixed effect approach will be explored in an attempt to provide a better estimate of time-
course of brain uptake, the total brain exposure over a dosing interval (AUC0-24) and the brain-
plasma tissue partitioning coefficient (Kpt). 
 
Cohort 1 will also assess for pharmacodynamic (PD) evidence of target inhibition in brain tissue. 
We will evaluate tumor tissue after treatment with abemaciclib for reduced RB1 signaling, 
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cellular proliferation, and increased cell death by immunohistochemistry for pRB1, Ki67, and 
cleaved caspase 3. The IHC effects will be evaluated by pathologist manual scoring of each 
marker as well as morphometric techniques to determine change relative to pre-abemaciclib 
biopsy which will also be stained. These results will be compared to a group of 15 patient 
samples who received treatment only with standard of care TMZ and RT. Results of the two 
cohorts will be compared statistically to determine whether significant changes are noted. 
 
The primary goal of Cohort 2 is to determine the therapeutic efficacy of abemaciclib as measured 
by PFS6. Treatment duration will be measured in 4-week cycles. Participants will remain on 
treatment until tumor progression, as long as there are no unacceptable toxicities. Responses will 
be assessed by clinical examinations every 4 weeks and MRI scans every 8 weeks. 
 
13.2 
Endpoints 
 
13.2.1  Cohort 1 
 
13.2.1.1 
Primary endpoint 
o Abemaciclib levels in tumor tissue 
o Pharmacokinetics 
13.2.1.2 
Secondary endpoints 
o Effects on tumor cell proliferation and tumor cell death 
o Safety 
13.2.1.3 
Exploratory endpoints 
o Effects of abemaciclib on primary GBM cell lines 
 
13.2.2 Cohort 2 
 
13.2.2.1 
Primary endpoint 
o PFS6 
13.2.2.2 
Secondary endpoints 
o Radiographic response rate 
o Median progression free survival 
o Overall survival  
o Pharmacokinetics 
o Safety 
13.2.3 Exploratory endpoints 
o Correlate benefit from abemaciclib treatment with molecular phenotype/genotype 
of tumor 
o Investigate mechanisms of resistance to abemaciclib by examining tumor tissue 
obtained from patients who progress on treatment, when available, with 
pretreatment tumor. 
 
13.3 
Sample Size/Accrual Rate 
 
A sample size of 15 participants is planned for the surgical sub-study (Cohort 1), with an accrual 
rate of 2-3 participants per month.  This results in an anticipated enrollment period of 5-8 months 
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for Cohort 1. 
 
Thirty-two participants will be accrued to Cohort 2 and will occur concurrently with Cohort 1. 
With an accrual rate of 4-5 participants per month, the anticipated enrollment period will be 7-9 
months for Cohort 2. 
 
The primary endpoint for Cohort 2 will be the proportion of participants who are progression 
free at 6 months (PFS6). Historical comparison data suggest that ineffective therapies in 
recurrent GBM have a PFS6 rate of approximately 9-16% (Lamborn et al., 2008; Wong et al., 
1999). The sample size was chosen to discriminate between 15% and 35% PFS6 rates for the 
GBM patients. With accrual of 32 GBM patients, the trial would be considered successful if 8 
achieved PFS6. This yields 0.92 power to detect a 35% PFS6 rate, with a 0.90 probability of 
rejecting the treatment regimen if the PFS6 rate is only 15%. 
 
Since the primary endpoint is PFS6, analyses will be not performed until the 6 month PFS status 
of all participants is determined (or the participant has been permanently censored for PFS for 
reasons such as loss-to-follow-up or initiation of alternative therapies). 
 
For the primary endpoint of PFS6, participants without documentation that they are progression 
free at 6 months – no progression at the 24 week scan – will be considered failures. Additional 
information about PFS will be provided using Kaplan Meier curves. For those analyses 
participants will be censored for PFS at the date of the last scheduled scan if they initiate 
alternative therapy or cease to have regularly scheduled follow up scans.   
 
13.4 
Analysis of Secondary and Exploratory Endpoints 
 
Response rate will be the proportion of participants with measurable disease who experience 
complete or partial radiographic response determined by the RANO Criteria (Wen et al., 2010). 
Progression free survival, PFS6, and overall survival will be calculated using standard statistical 
methods. Safety will be summarized using descriptive statistics. Participants in Cohort 2 will not 
be replaced for any reason. If a subject enrolled in Cohort 1 is found at the time of on-treatment 
re-resection to have only necrosis and not recurrent disease, then s/he may remain on treatment 
but should be replaced for evaluation of endpoints.  
 
In Cohort 1 & 2 plasma, and Cohort 1 tumor tissue levels of abemaciclib will be determined by 
liquid chromatography coupled with tandem mass spectrometry. Descriptive details of steady-
state trough plasma levels, CSF and tumor tissue concentrations and tumor tissue to plasma 
ratios will be provided.  
 
Other pharmacodynamic studies including immunohistochemistry and quantitative IHC analysis 
will be performed as in Section 9.0. Effects of abemaciclib on tumor cell proliferation and tumor 
cell death will be measured using immunohistochemistry for pRB1, Ki-67 and Cleaved Caspase 
3. In general the pharmacodynamic and neuro-imaging results will be summarized in a 
descriptive manner with comparison between pre- and post-treatment assay results when 
possible. 
 
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Beyond the assessment of “success”, more detailed analyses of the biological correlate data are 
exploratory. The statistical analysis will depend on the amount and quality of the data obtained 
as well as the overall success of the treatment. 
 
13.5 
Reporting and Exclusions 
 
Evaluation of toxicity. All participants who receive at least one dose of study treatment will be 
evaluable for toxicity from the time of their first treatment. 
Evaluation of response.  Only those participants who have measurable disease present at baseline 
and have received at least one dose of therapy will be considered evaluable for response.  
Evaluation of other efficacy endpoints. All participants who receive at least one dose of study 
treatment (post surgery for those in Cohort 1) will be included in analyses of all other endpoints. 
Time-to-event endpoints will be measured from first dose date (first post-surgery dose date for 
those in Cohort 1). 
 
14. DISCIPLINE REVIEW 
 
14.1 
Central Pathology Review 
 
At screening archival tumor tissue (as described in section 3.1.10) from the pre-registration surgery 
must be submitted for review along with accompanying pathology, surgical, and genomic profiling 
reports. The purpose of this review is to verify the histologic diagnosis, loss of CDKN2A/B, and 
intact RB. 
 
Section 9.2 contains details regarding shipping and handling. 
 
If the participant’s slides have been reviewed on a previous IVY study and there has been no 
interim surgery or biopsy the slides do not need to be re-submitted. The site must submit a copy 
of the previous submission forms with the review results to the IVY central office as 
documentation for the new study. 
 
Central pathology and molecular review will be performed at DFCI by Dr. Keith L. Ligon, MD, 
PhD or designee. Materials for pathologic study will be stored in the lab of Dr. Ligon following 
participant registration in the trial.  
 
The submitting institution is responsible for the costs of shipping and handling. 
 
14.2 
Central Radiology Review 
 
Please see section 11.6 for details.  
 
15. PUBLICATION PLAN AND DISCLOSURE POLICY 
 
Participant medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted herein is prohibited. Data generated by this study must be available 
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for inspection upon request by representatives of the FDA, national and local health authorities, 
Pharmaceutical company providing the agent, and the IRB for each study site, if appropriate. The 
intention is to publish the results of this study in a medical journal such as Journal of Clinical 
Oncology or Neuro-Oncology. Results may be presented at national meetings of the American 
Society for Clinical Oncology and/or Society for Neuro-Oncology. Results will be made publicly 
available as required by law. 
 
Clinical Trial Data Bank 
 
The DF/HCC Principal Investigator (Dr. Eudocia Quant Lee) or designee will register this 
clinical trial at www.clinicaltrials.gov, the US National Library of Medicine website prior to 
initiation of the study. This website provides regularly updated information about US 
government and privately supported clinical research in human volunteers.  In addition, the 
DF/HCC Principal Investigator or designee will make the results of this study publicly 
accessible by publication and by posting the results on www.clinicaltrials.gov  
 
 
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REFERENCES 
 
Brennan, C. W., Verhaak, R. G., McKenna, A., Campos, B., Noushmehr, H., Salama, S. R., . . . 
Network, T. R. (2013). The somatic genomic landscape of glioblastoma. Cell, 155(2), 
462-477. doi:10.1016/j.cell.2013.09.034 
Cen, L., Carlson, B. L., Schroeder, M. A., Ostrem, J. L., Kitange, G. J., Mladek, A. C., . . . 
Sarkaria, J. N. (2012). p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase 
inhibitor PD0332991 in glioblastoma xenograft cells. Neuro Oncol, 14(7), 870-881. 
doi:10.1093/neuonc/nos114 
Craig, J. M., Vena, N., Ramkissoon, S., Idbaih, A., Fouse, S. D., Ozek, M., . . . Ligon, A. H. 
(2012). DNA fragmentation simulation method (FSM) and fragment size matching 
improve aCGH performance of FFPE tissues. PloS one, 7(6), e38881. 
doi:10.1371/journal.pone.0038881 
Dunn, G. P., Rinne, M. L., Wykosky, J., Genovese, G., Quayle, S. N., Dunn, I. F., . . . Hahn, W. 
C. (2012). Emerging insights into the molecular and cellular basis of glioblastoma. Genes 
Dev, 26(8), 756-784. doi:10.1101/gad.187922.112 
Goel, S., DeCristo, M. J., Watt, A. C., BrinJones, H., Sceneay, J., Li, B. B., . . . Zhao, J. J. 
(2017). CDK4/6 inhibition triggers anti-tumour immunity. Nature, 548(7668), 471-475. 
doi:10.1038/nature23465 
Lamborn, K. R., Yung, W. K., Chang, S. M., Wen, P. Y., Cloughesy, T. F., DeAngelis, L. M., . . 
. North American Brain Tumor, C. (2008). Progression-free survival: an important end 
point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol, 10(2), 162-
170. doi:10.1215/15228517-2007-062 
Michaud, K., Solomon, D. A., Oermann, E., Kim, J. S., Zhong, W. Z., Prados, M. D., . . . 
Waldman, T. (2010). Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 
arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res, 70(8), 
3228-3238. doi:10.1158/0008-5472.CAN-09-4559 
Ostrom, Q. T., Gittleman, H., Liao, P., Rouse, C., Chen, Y., Dowling, J., . . . Barnholtz-Sloan, J. 
(2014). CBTRUS statistical report: primary brain and central nervous system tumors 
diagnosed in the United States in 2007-2011. Neuro Oncol, 16 Suppl 4, iv1-63. 
doi:10.1093/neuonc/nou223 
Raub, T. J., Wishart, G. N., Kulanthaivel, P., Staton, B. A., Ajamie, R. T., Sawada, G. A., . . . De 
Dios, A. (2015). Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and 
the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with 
Temozolomide in an Intracranial Glioblastoma Xenograft. Drug Metab Dispos, 43(9), 
1360-1371. doi:10.1124/dmd.114.062745 
Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J., . . . 
National Cancer Institute of Canada Clinical Trials, G. (2005). Radiotherapy plus 
concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med, 352(10), 987-
996. doi:10.1056/NEJMoa043330 
Wagle, N., Berger, M. F., Davis, M. J., Blumenstiel, B., Defelice, M., Pochanard, P., . . . 
Garraway, L. A. (2012). High-throughput detection of actionable genomic alterations in 
clinical tumor samples by targeted, massively parallel sequencing. Cancer Discovery, 
2(1), 82-93. doi:10.1158/2159-8290.CD-11-0184 
Wen, P. Y., & Kesari, S. (2008). Malignant gliomas in adults. N Engl J Med, 359(5), 492-507.  
Wen, P. Y., Macdonald, D. R., Reardon, D. A., Cloughesy, T. F., Sorensen, A. G., Galanis, E., . . 
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. Chang, S. M. (2010). Updated response assessment criteria for high-grade gliomas: 
response assessment in neuro-oncology working group. J Clin Oncol, 28(11), 1963-1972.  
Wiedemeyer, R., Brennan, C., Heffernan, T. P., Xiao, Y., Mahoney, J., Protopopov, A., . . . Chin, 
L. (2008). Feedback circuit among INK4 tumor suppressors constrains human 
glioblastoma development. Cancer Cell, 13(4), 355-364. doi:10.1016/j.ccr.2008.02.010 
Wong, E. T., Hess, K. R., Gleason, M. J., Jaeckle, K. A., Kyritsis, A. P., Prados, M. D., . . . 
Yung, W. K. (1999). Outcomes and prognostic factors in recurrent glioma patients 
enrolled onto phase II clinical trials. J Clin Oncol, 17(8), 2572-2578.  
 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
0 
Dead. 
 
 
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APPENDIX B 
MULTI-CENTER DSMP 
 
 
 
 
 
 
 
 
 
 
 
DFCI IRB Protocol #: 16-383 
 
 
 
 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
1.0 
INTRODUCTION .............................................................................................................83 
1.1 
Purpose ...................................................................................................................83 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ..................................83 
2.0 
GENERAL ROLES AND RESPONSIBILITIES .............................................................84 
2.1 
DF/HCC Sponsor ...................................................................................................84 
2.2 
Coordinating Center ...............................................................................................85 
2.3 
Participating Institution ..........................................................................................85 
3.0 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................86 
3.1 
Protocol Distribution ..............................................................................................86 
3.2 
Protocol Revisions and Closures ...........................................................................86 
3.3 
Informed Consent Requirements ...........................................................................87 
3.4 
IRB Documentation ...............................................................................................87 
3.5 
IRB Re-Approval ...................................................................................................87 
3.6 
Participant Confidentiality and Authorization Statement ......................................87 
3.7 
DF/HCC Multi-Center Protocol Registration Policy .............................................88 
3.8 
DF/HCC Protocol Case Number ............................................................................90 
3.9 
Protocol Deviations, Exceptions and Violations ...................................................91 
3.10 
Safety Assessments and Toxicity Monitoring .......................................................92 
3.11 
Data Management ..................................................................................................92 
4.0 
REQUISITIONING INVESTIGATIONAL DRUG..........................................................93 
5.0 
MONITORING: QUALITY CONTROL ..........................................................................93 
5.1 
Ongoing Monitoring of Protocol Compliance .......................................................93 
5.2 
Evaluation of Participating Institution Performance ..............................................97 
5.3 
Accrual Monitoring............................................................................. ...................97 
6.0 
AUDITING: QUALITY ASSURANCE ...........................................................................97 
6.1 
Audit Plan: DF/HCC Sponsored Trials..................................................................97 
6.2 
Audit Notification ..................................................................................................97 
6.3 
Audit Reports .........................................................................................................98 
6.4 
Participating Institution Performance ....................................................................98 
 
 
 
 
 
 
 
 
 
 
 
 
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1.0 INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol.  
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.        
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  Among the Dana-Farber/Harvard Cancer Center sites (DFCI, MGH, 
BIDMC, CHB, BWH), the Dana-Farber Cancer Institute will be the Lead Institution and 
will be responsible for the coordination, development, submission, and approval of a 
protocol as well as its subsequent amendments per the DFCI IRB and applicable regulatory 
guidelines (FDA, etc.). The Lead Institution is the home of the Overall PI. 
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. The DF/HCC 
Sponsor has ultimate authority over the protocol and is responsible for the conduct of the 
study at DF/HCC and all Participating Institutions. For this protocol the DF/HCC Sponsor 
is the same person as the DF/HCC Overall Principal Investigator. 
 
Participating Institution:  An institution that desires to collaborate with DF/HCC and 
commits to accruing participants to the DF/HCC protocol.  The Participating Institution 
acknowledges the DF/HCC Sponsor as having the ultimate authority and responsibility for 
the overall conduct of the study.    
 
Coordinating Center: The entity that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory guidelines. In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol.  
  
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible for 
registering human subjects for trials, ensuring high-quality standards are used for data 
collection and the ongoing management of clinical trials, auditing, and data and safety 
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monitoring.  ODQ also coordinates quality assurance efforts related to multi-center clinical 
research. 
 
DF/HCC Research Informatics for Operations (RIO): A group within DF/HCC 
responsible for providing a comprehensive data management platform for managing clinical 
trial data. 
 
 
2.0 GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general responsibilities:  
 
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, Eudocia Quant Lee, MD, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives 
adequate protocol training and/or a Site Initiation Visit prior to enrolling participants 
and throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language. 
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(i.e. FDA) reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with FDA (investigator-held IND trials), as applicable. 
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior 
to extending the protocol to that site.  
• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements. 
 
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2.2 Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development  
• Maintain FDA correspondence, as applicable. 
• Review registration materials for eligibility and register participants from 
Participating Institutions with DF/HCC ODQ. 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed.  
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violations submitted by Participating Institutions and provide  to the 
DF/HCC Sponsor for timely review.   
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements 
that they will be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or virtual 
monitoring.  
• Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federal Wide Assurances (FWAs) for all 
sites, all SAE submissions, Screening Logs for all sites, IRB approved consents for 
all sites.  
• Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation of all relevant communications. 
 
2.3 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not limited 
to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial 
as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
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• Register participants through the Coordinating Center prior to beginning research 
related activities.  
• Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements.  
• Submit protocol deviations and violations to local IRB per local requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings.  
• Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
 
3.0 DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB approved 
and implemented within 90 days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating 
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Center, will update the Participating Institutions on an ongoing basis about protocol 
accrual data so that they will be aware of imminent protocol closures. 
 
3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols.  This document will be provided separately to each Participating 
Institution. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that 
only attending physicians obtain informed consent and re-consent to interventional trials 
(i.e. drug and/or device trials).   
 
3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB  
• Participating Institution’s IRB approval for all amendments 
• Annual approval letters by the Participating Institution’s IRB  
 
3.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval date.   
 
3.6 Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPAA). Any 
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information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course 
of a study, the study participant must sign an authorization statement.  This authorization 
statement may or may not be separate from the informed consent document.  The 
Coordinating Center, with the approval from the DFCI IRB, will provide a consent template, 
with information regarding authorization for the disclosure of protected health information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials.  However, because of the nature of these trials, certain protected health information 
must be collected.  DF/HCC has chosen to use authorizations, signed by the participant in 
the trial, rather than limited data sets with data use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should 
be de-identified. It is recommended that the assigned DF/HCC ODQ case number (as 
described below). Participant initials may be included or retained for cross verification of 
identification 
 
3.7 DF/HCC Multi-Center Protocol Registration Policy 
Eligible participants will be registered onto trial with the DF/HCC Office of Data 
Quality (ODQ) central registration system (by a Coordinating Center specialist, if 
participant is at a non-DF/HCC site). Registration with ODQ must occur prior to the 
initiation of therapy. Any participant not registered to the protocol before treatment 
begins will be considered ineligible and registration will be denied.  
 
 
 
 
A qualified member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist.  
Issues that would cause treatment delays should be discussed with the Principal 
Investigator. If a participant does not receive protocol therapy following registration, the 
participant’s protocol status must be changed.  Notify the ODQ Registrar (a Coordinating 
Center specialist, if participant is at a non-DF/HCC site) of participant status changes as 
soon as possible.  
 
In order to register a participant onto study, the following must be done: 
• Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments. 
• Complete the protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical/research record. To be eligible for 
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registration to the study, the participant must meet each inclusion and exclusion 
criteria listed on the eligibility checklist. 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for 
the treatment study. Registration to both treatment and ancillary studies will not be 
completed if eligibility requirements are not met for all studies. 
 
Treatment may not begin without confirmation from the Coordinating Center 
that the participant has been registered.  
 
3.7.1 Participant Registration at a non-DF/HCC Site 
 
To register a participant at any non-DF/HCC site, the subsequent procedure is to be 
followed: 
 
1. The participating site’s data manager/coordinator/research nurse should contact the 
lead-site Designee (Multi-Center Coordinating Center specialist) via telephone or 
email to: 
•   Notify regarding the pending registration 
•   Confirm the methods of sending documents and communication for registration 
•    Communicate desired timeline of the registration (i.e. within the hour, the next day) 
via e-mail to NeuroOnc_Coor@dfci.harvard.edu   
 
2. The data manager/coordinator/research nurse should then send the following 
documents to the Coordinating Center specialist: 
• Completed DF/HCC study specific Eligibility Checklist 
• Copy of protocol required test results (e.g. coagulation studies, hematology 
panel, serum pregnancy test, serum chemistry panel, urinalysis -- all as 
applicable per protocol) 
• Copy of the pathology and surgical reports 
• List of current concomitant medications (obtained within the protocol-
specified screening window) including sign/date by RN/other clinician and 
documentation of when reviewed/confirmed with patient  
• Copy of signed informed consent form 
• Copy of signed HIPAA authorization form (if separate from the informed 
consent document) 
• Copy of clinic note(s) and other medical records that document consenting 
process, screening and eligibility, if available*** 
 
Documents will be transmitted via one of the following methods: 
• Scanned and emailed to: NeuroOnc_Coor@dfci.harvard.edu  
• Faxed to: 617-394-2683 
 
*** The Coordinating Center Specialists would like to review and monitor participant 
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eligibility, informed consent, screening and baseline assessments on all participants.  
Providing a complete set of source documents prior to registration may delay 
registration.  Participating Institutions will work with the Coordinating Center 
Specialists to determine what documents may feasibly be available for review prior to 
enrollment, and these documents are to be provided for pre-enrollment review.  A 
complete set of documents will be provided to the Coordinating Center after 
registration; the timeline will be determined by the Coordinating Center Specialist 
based on the study team’s experience with the trial and prior monitoring findings.  If 
there are persistent issues with eligibility at a site or with a study overall, the 
Coordinating Center may require that all source documentation relevant to participant 
eligibility be provided prior to proceeding with participant registration.  
2. After having received all transferred documentation, the Designee (Coordinating 
Center specialist) will review the documents to verify eligibility, and notify the 
participating site of the result. 
3. The Coordinating Center Designee will register the participant with ODQ Registrar, 
and subsequently inform the participating site of the successful registration via Fax 
or email, to include: 
• Participant case number 
• Applicable Dose Treatment level and treatment arm assignment 
4. The Coordinating Center Designee will follow-up to confirm registration. 
 
3.7.2 Initiation of Therapy 
 
Participants must be registered with the DF/HCC ODQ before receiving treatment.  
Treatment may not be initiated until the Participating Institution receives confirmation of 
the participant’s registration from the Coordinating Center. Therapy must be initiated per 
protocol guidelines.  The DF/HCC Sponsor and DFCI IRB must be notified of any violations 
to this policy. 
 
3.7.3 Eligibility Exceptions 
 
The DF/HCC ODQ will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC ODQ requires each participating institution to 
fully comply with this requirement. 
 
3.8 DF/HCC Protocol Case Number 
 
At the time of registration, ODQ requires the following identifiers for all subjects: initials, 
date of birth, gender, race and ethnicity.  Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 
number. 
Participating 
Institutions 
should 
submit 
all 
de-identified 
subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.  
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3.9 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy 
for reporting to their local IRB. 
 
3.9.1 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
  
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB 
prior to its initiation or implementation.  
 
 
3.9.2  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the Overall PI and DFCI IRB. Upon 
DFCI IRB approval the deviation is submitted to the Participating Institution IRB, per 
institutional policy. A copy of the Participating Institution’s IRB report and determination 
will be forwarded to the Coordinating Center within 10 business days after the original 
submission.  
 
Protocol violations occurring at a Participating Institution will be submitted to that site’s 
own IRB per the IRB’s reporting policy.  Whether or not a violation needs to be reported to 
the local IRB, notification to the Coordinating Center of any violation should occur in a 
timely manner.  If a report is made to the Participating Institution’s IRB, the report and 
determination should also be forwarded to the Coordinating Center in a timely manner.  
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Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
 
3.10 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents will be evaluated for safety.   The safety 
parameters include all laboratory tests and hematological abnormalities, physical 
examination findings, and spontaneous reports of adverse events reported by participants.  
All toxicities encountered during the study will be evaluated according to the NCI criteria 
specified in the protocol. Life-threatening toxicities must be reported immediately to the 
DF/HCC Sponsor via the Coordinating Center and IRB, both DFCI and local as applicable.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.10.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 7.  
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Advert Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Intuitions will review and submit to their IRB according to their institutional 
policies and procedures. 
 
3.10.2 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions.  Participating Institutions will  
review and submit to their IRB according to their intuitional policies and procedures. 
  
 
 
3.11 Data Management 
 
The DF/HCC CTRIO develops case report forms (eCRFs), for use with the protocol.  These 
forms are designed to collect data for the study. The DF/HCC CTRIO provides a web based 
training for eCRF users. 
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3.11.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in accordance 
with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC ODQ Data Analyst, Coordinating 
Center or designee.  Responses to all queries should be completed and submitted within 14 
calendar days.  Responses may be returned within the electronic data capture (eDC) system.  
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the Coordinating Center noting the missing forms.  These reports 
are compiled by the DF/HCC ODQ and distributed on a monthly basis. Required timelines 
for data submission based on form type are defined in protocol section 12.1.2. 
 
 
4.0 REQUISITIONING INVESTIGATIONAL DRUG 
Participating Institutions will order their own investigational agent (Abemaciclib) directly 
from Lilly using the Drug Supply Request Form.  Please allow for 3-5 business days for drug 
to arrive after the order is submitted.  Additional information for ordering Abemaciclib can 
be found in Section 8.1.9 of the protocol body.  The Participating Institution will ensure that 
the pharmacy will be able to receive and store the agent according to state and federal 
guidelines. The local IRB should be kept informed of who will supply the agent (i.e., Lilly) 
so that any regulatory responsibilities can be met in a timely fashion.   
 
 
5.0 MONITORING: QUALITY CONTROL 
 
Monitoring and oversight of a clinical trial are federally mandated for all IND held trials. 
This quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy and the protection of the rights and welfare of participants. The 
Coordinating Center, with the aid of the ODQ provides quality control oversight for the 
protocol. 
 
5.1 Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring.   Participating Institutions may also be subject to on-
site monitoring conducted by the Coordinating Center.  
 
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The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring will occur before the clinical phase of the 
protocol begins, continue during protocol performance and through study completion. 
Additional monitoring practices may include but are not limited to; source verification, 
review and analysis of the following: eligibility requirements of all participants , informed 
consent procedures, adverse events and all associated documentation, study drug 
administration/treatment, regulatory files, protocol departures, pharmacy records, response 
assessments, and data management.  
Remote monitoring of participant eligibility, human subject’s protection via the initial 
informed consent process, and screening evaluation completion will occur via a two stage 
process. 
• Prior to registering each participant, a Coordinating Center Specialist will review the 
source documentation provided in the enrollment packet (see Section B 3.7.1) to 
confirm, (a) that based on all objective measurements (lab tests; pathology report) 
that the prospective participant is eligible, (b) that the objective measurements were 
performed per protocol within the appropriate protocol-defined windows, (c) that the 
prospective participant does not have concomitant medication that precludes 
eligibility, and, if documentation is provided, (d) that the consenting process was 
adequate/adequately documented, (e) that the participant met criteria for eligibility.  
Furthermore, using the Eligibility Screening Worksheet, the Specialist will verify that 
the investigator has indicated that he/she has reviewed and confirmed as “eligible” 
the prospective participant 
• The Specialist will review the second set of participant-specific source documents 
provided by study teams (see Section B 3.7.1) to confirm that (a) all screening and 
baseline assessments were completed per protocol, including AE assessment, and 
documented appropriately, (b) that all eligibility criteria were met and appropriately 
documented, and, if not previously reviewed, (c) that the consenting process was 
adequate/adequately documented.  The timeline for this review will be based on the 
experience with the study team, and the study team’s experience with the protocol.       
Interim monitoring visits will occur on the following schedule: 
• Once a site has registered a participant, up until all participants (and planned 
participants) have discontinued taking study agent (may be in follow-up), interim 
monitoring visits will occur at least twice per year, alternating between on-site visits 
and virtual monitoring visits.  The first on-site interim monitoring visit will occur 
approximately two months after the registration of the site’s first participant.  
• Once a site is closed to accrual and all participants have discontinued study agent, 
interim monitoring visits will occur virtually, and on-site as needed, at least annually 
until study completion.   
On-site and remote monitoring visits may include but are not limited to the following: 
• Adverse events and altered results 
• Response assessment including measurements and clinical assessments 
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• Study drug administration and accountability, to include a visit to the pharmacy  
• Concomitant medications 
• Re-consenting 
• Presence of key documents: original consent, eligibility and screening source 
information, registration confirmation, off-treatment form, off-study form, transfer 
of samples 
• Reason off treatment and reason off study 
• Regulatory binder: accessibility, organization, random sampling for relevant 
documents and correspondence with the trial master file. 
• Visit with the site’s principal investigator: 
o Review of site’s accrual rate and, when possible, sign-off on the 
screening/enrollment log to date 
o Review of deviations and violations, and, when possible, sign-off on the 
deviation/violation log 
o General study progress 
• Timeliness of data completion (at the time of the INTERIM MONITORING VISIT 
and history since last report) 
• Attendance at teleconferences since last report 
• Completion of study procedures per protocol (procedures complete and within 
windows) 
• Agreement between recorded results and the AE log. 
• Analysis of data for any events that met criteria for Reportable Adverse Events, dose 
holds, dose reductions, or discontinuation of treatment. 
• Review the eDC for any Reportable Adverse Events, holds, dose reductions, and 
discontinuation of treatment to ensure the justification and follow-up are sufficiently 
documented in the eDC. 
• Agreement between drug accountability records and drug administration 
• Agreement and completion of the trial master file 
Timely transfer of copies of regulatory documents including pharmacy records.  The 
Coordinating Center is mandated to maintain a Trial Master File, which is a copy of the 
site’s regulatory binder. 
• Regulatory documents should be sent electronically to the Coordinating Center in 
lieu of being collected at the time of the monitoring visit; they should be sent upon 
receipt/creation to the Coordinating Center, and not wait until time of request. 
• Original forms (i.e. 1572s, protocol receipts etc.) should be maintained with the site’s 
regulatory binder until requested by the Coordinating Center.  When possible, the 
Coordinating Center will provide a stamped certified copy of the original for the site’s 
regulatory binder. 
• Special consideration should be placed on the timely transfer of pharmacy regulatory 
binder documents, since the Coordinating Center is responsible for tracking all study 
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agent.  Copies of DARs and shipping receipts should be provided to the Coordinating 
Center via electronic submission on request.  The Coordinating Center is to be copied 
on all drug requests.  
Regular all-sites teleconferences to occur at least monthly, bi-weekly when needed. 
During the teleconferences, sites will be expected to convey the following information: 
• Updates on participants taking agent: holds, dose reductions, significant events, how 
participant is doing, whether or not underwent re-consenting 
• Protocol status – which version is being used, and the status of any amendments 
• Any Reportable Adverse Events or Deviations/violations that have yet to be 
communicated to the sponsor team (informing the sponsor should not wait for the 
call, and the call does not supplant communicating the events via the regular email 
methods of communication). 
• Review of prospective participants 
If sites are not able to have a representative participant, they should email this information. 
During the teleconferences, the Coordinating Center Specialist will provide the following 
information at least monthly: 
• Accrual/enrollment updates 
• Pending amendments 
• Safety reports circulated or to be circulated 
• ODQ-generated numbers and percentage of missing of missing forms, number of 
open queries with date of oldest open query, and, for participants on treatment, the 
date of their last study agent form 
• To be updated at least every three months: for participants in follow up, the date of 
their last follow-up. 
• Updates (newly discovered events) of deviations, violations 
• Updates of Reportable Adverse Events  
Monthly circulation of Central Logs and Missing Forms Reports.  Approximately 
monthly, and usually at the time of the teleconferences, the Coordinating Center Specialist 
will circulate the updates to the Central Screening Enrollment Log, Central 
Deviation/violation log, Central Reportable Adverse Event Log, and ODQ generated 
Missing Forms Reports. 
Initial training.  To aid with protocol compliance, the Coordinating Center will provide a 
teleconference site initiation visit (approximately 3 hours) and operations manual (as 
needed) prior to activation of the study at each site.   In addition, the Coordinating Center 
will provide an overview of the eCRFs with appropriate study team members, after each 
site has registered their first participant.    
The Coordinating Center will be available to all sites’ study team members for resolving 
questions concerns and facilitating compliance.  
Because of limited on-site monitoring visits, participating sites will be required to submit 
(either electronically or via paper) requested source documents to the Coordinating Center 
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for source verification.  
 
5.2 Evaluation of Participating Institution Performance 
 
5.2.1 Monitoring Reports 
 
The DF/HCC Sponsor will be provided with all monitoring reports for on-site and remote 
monitoring of Participating Institutions for review to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at Participating Institutions that 
are unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. Participating Institutions may also be subject to an audit as determined by the 
DF/HCC Sponsor. 
 
5.3 Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting 
their accrual expectations may be subject to termination. 
 
As this is a Phase II study, Participating Institutions accrual requirement of 3 participants 
per site annually will be implemented. 
 
 
6.0 AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents.  Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR). 
 
6.1 Audit Plan: DF/HCC Sponsored Trials 
 
One on-site audit will be scheduled by the ODQ, assuming at least three participants have 
been treated on protocol at the site. Approximately 3-4 participants would be audited at the 
site over a 2 day period.  If violations which impact participant safety or the integrity of the 
study are found, more participant records may be audited.  
 
 
6.2 Audit Notification 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve this 
protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
98 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after the 
audit date.  
 
6.3 Audit Reports 
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the audit 
rating and final report. Conditional approval could require the DF/HCC Sponsor to 
implement recommendations or require further follow-up.  For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.4 Participating Institution Performance 
 
The DF/HCC Sponsor and DFCI IRB are charged with considering the totality of an 
institution’s performance in considering institutional participation in the DF/HCC Multi-
Center protocol. 
 
6.4.1 Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. A 
DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above. 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
99 
APPENDIX C  
REPORTABLE AE COVERSHEET 
DF/HCC Protocol No. 16-383     
 
Eli Lilly Protocol No. I3Y-MC-009 
Date:____________________      
 
Number of pages including cover sheet:______ 
Please check off recipient of this AE: 
        Eudocia Quant Lee, MD (Overall PI) at Dana-Farber Cancer Institute Coordinating Center 
    Email: NeuroOnc_SAE@dfci.harvard.edu 
        Eli Lilly and Company  
              MAILINDATA_GSMTINDY@LILLY.COM 
 
From: 
Institution: 
Phone No.: 
Fax No.: 
 
Participant No. and Initials: 
Date Event Met Reporting Criteria (as defined per protocol): 
Type of Report:    Initial   Follow-up 
Will this event be reported to your local IRB?  Yes   No 
 
Event #1 Description: 
Event #2 Description (if applicable): 
 
NOTE: Please use additional sheet if > 2 events are being 
reported 
Meets Definition of Serious AE:    
   Serious        Non-serious 
Meets Definition of Serious AE:    
   Serious         Non-serious 
Toxicity Grade:      
G1/mild   G2/moderate   G3/severe   
G4/life threatening   G5 
Toxicity Grade:      
G1/mild   G2/moderate   G3/severe   
G4/life threatening   G5 
Historical/Known Correlation to Abemaciclib:    
Expected   Unexpected  
NOTE: Please refer to protocol section 6.1 
Historical/Known Correlation to Abemaciclib:    
Expected   Unexpected   
NOTE: Please refer to protocol section 6.1 
Attribution to Abemaciclib:     
Unrelated   Unlikely    Possible    
Probable    Definite 
Attribution to Abemaciclib:     
Unrelated   Unlikely    Possible    
Probable    Definite 
 
Reporting Investigator (please print): 
 
Signature of Reporting Investigator: ___________________________   Date: ______________ 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
100 
 
APPENDIX D 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Please see Section 5.4 for detailed instructions on concomitant medications, including use in 
clinically required situations.  Please note that these lists may not be comprehensive.  
 
Table D-1: List of CYP3A Inhibitors and CYP3A Inducers 
CYP3A4,5,7 inhibitors 
CYP3A4,5,7 inducers 
indinavir1 
carbamazepine 
nelfinavir1 
efavirenz 
ritonavir1 
nevirapine 
clarithromycin1 
phenobarbital 
itraconazole1 
phenytoin 
ketoconazole1 
pioglitazone 
nefazodone1 
rifabutin 
erythromycin2 
rifampin 
grapefruit juice2 
St. John’s Wort 
verapamil2 
troglitazone 
suboxone2 
 
diltiazem2 
 
cimetidine3 
 
amiodarone 
 
NOT azithromycin 
 
flyvoxamine 
 
troleandomycin 
 
voriconazole 
 
1.  A Strong inhibitor is one that causes a > 5-fold increase in the plasma AUC values or more than 80% decrease in 
clearance.  Strong inhibitors are prohibited per protocol section 5.4. 
2.  A Moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC values or 50-80% decrease in 
clearance. 
3. A Weak inhibitor is one that causes a > 1.25-fold but < 2-fold increase in the plasma AUC values or 20-50% 
decrease in clearance. 
This list of CYP3A inhibitors and inducers was compiled from the Indiana University School of Medicine’s P450 Drug 
Interaction Table: Abbreviated “Clinically Relevant” Table.  For the most comprehensive and up-to-date list, please go 
to http://medicine.iupui.edu/clinpharm/ddis/ . 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine 
(2007). "/clinpharm/ddis/clinical-table/" Accessed October 2015 
 
 
 
 
 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
101 
 
 
Table D-2: List of CYP450 Substrates to be used with caution 
CYP1A2 
CYP2B6 
CYP2C8 
CYP2C9 
CYP2D6 
CYP3A4,5,7  
clozapine 
artemisinin 
paclitaxel 
NSAIDs: 
Beta Blockers: 
Macrolide antibiotics: 
cyclobenzaprine 
bupropion 
torsemide 
diclofenac 
carvedilol 
clarithromycin 
duloxetine 
cyclophosphamide 
amodiaquine 
ibuprofen 
S-metoprolol 
erythromycin 
fluvoxamine 
efavirenz 
cerivastatin 
naproxen 
propafenone 
NOT azithromycin 
haloperidol 
Iiosfamide 
repaglinide 
piroxicam 
timolol 
telithromycin 
imipramine 
ketamine 
 
Oral Hypoglycemics: 
Antidepressants: 
Anti-arrhythmics: 
mexiletine 
meperidine 
 
tolbutamide 
amitriptyline 
quinidine→3-OH 
nabumetone 
methadone 
 
glipizide 
clomipramine 
Benzodiazepines: 
naproxen 
nevirapine 
 
glyburide 
desipramine 
alprazolam 
olanzapine 
propofol 
 
Angiotensin II 
Blockers: 
duloxetine 
diazepam→3-OH 
riluzole 
selegiline 
 
iosartan 
fluoxetine 
midazolam 
tacrine 
 
 
irbesartan 
imipramine 
triazolam 
theophylline 
 
 
Others: 
paroxetine 
Immune Modulators: 
tizanidine 
 
 
celecoxib 
Antipsychotics: 
cyclosporine 
triamterene 
 
 
fluvastatin 
haloperidol 
tacrolimus 
zileuton 
 
 
phenytoin 
risperidone 
sirolimus 
zolmitriptan 
 
 
rosiglitazone 
thioridazine 
HIV Antivirals: 
 
 
 
torsemide 
Others: 
indinavir 
 
 
 
valproic acid 
aripiprazole 
ritonavir 
 
 
 
warfarin 
atomoxetine 
saquinavir 
 
 
 
zafirlukast 
codeine 
nevirapine 
 
 
 
 
dextromethorphan 
Prokinetics: 
 
 
 
 
doxepine 
cisapride 
 
 
 
 
flecainide 
Antihistamines: 
 
 
 
 
mexiletine 
astemizole 
 
 
 
 
ondansetron 
chlorpheniramine 
 
 
 
 
oxycodone 
Calcium Channel 
Blockers: 
 
 
 
 
risperidone 
amlodipine 
 
 
 
 
tamoxifen 
diltiazem 
 
 
 
 
tramadol 
felodipine 
 
 
 
 
venlafaxine 
nisoldipine 
 
 
 
 
 
nitrendipine 
 
 
 
 
 
verapamil 
 
 
 
 
 
HMG CoA Reductase 
Inhibitors: 
 
 
 
 
 
atorvastatin 
 
 
 
 
 
lovastatin 
 
 
 
 
 
NOT pravastatin 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
 
102 
 
 
 
 
 
NOT rosuvastatin 
 
 
 
 
 
simvastatin 
 
 
 
 
 
PDE-5 Inhibitors: 
 
 
 
 
 
sildenafil 
 
 
 
 
 
tadalafil 
 
 
 
 
 
vardenafil 
 
 
 
 
 
Others: 
 
 
 
 
 
alfentanyl 
 
 
 
 
 
aripiprazole 
 
 
 
 
 
Boceprevir 
 
 
 
 
 
busprione 
 
 
 
 
 
carbamazepine 
 
 
 
 
 
gleevec 
 
 
 
 
 
haloperidol 
 
 
 
 
 
pimozide 
 
 
 
 
 
quinine 
 
 
 
 
 
tamoxifen 
 
 
 
 
 
telaprevir 
 
 
 
 
 
trazodone 
 
 
 
 
 
vincristine 
This list of CYP substrates was compiled from the Indiana University School of Medicine’s P450 Drug Interaction Table: 
Abbreviated “Clinically Relevant” Table.  For the most comprehensive and up-to-date list, please go to 
http://medicine.iupui.edu/clinpharm/ddis/ . 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). 
"/clinpharm/ddis/clinical-table/" Accessed October 2015 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
103 
 
APPENDIX E 
ABEMACICLIB DOSING INSTRUCTIONS & DRUG DIARY (Post-Surgery Cohort 1 & Cohort 2)  
To be completed by study personnel:     
Patient ID #_______  Patient Initials: ______  Cycle #: _____ Month & Year: _________    Abemaciclib Dose: ______mg, two times a day.   
TAKE ____  pill(s) in the morning and ____ pill(s) in the evening.  
Abemaciclib Description: 
• 
Your study drug (Abemaciclib) is supplied as 50 mg mixture beige tablet. 
Abemaciclib Instructions – When and How: 
• 
Take study drug (Abemaciclib) twice a day, once in the morning and once in the evening. 
• 
Take the drugs at approximately the same time each morning and evening, so that you are taking the drugs 12 hours apart.   At the start of cycles 2, 3 and 
4 you will be asked to take your morning abemaciclib after your clinic visit.   
• 
Take the pill(s) with a glass of water and swallow them whole; do not chew them or crush them. Abemaciclib can be taken with or without food. 
• 
Do not skip any doses. 
• 
If you forget to take your pills in the morning you can take your missed dose up to 6 hours after your normally scheduled time.  If it has been more than 6 
hours, skip the dose and take the next scheduled dose at the usual time in the evening (one dose only).  Please call your study nurse or doctor to discuss 
missed doses.  
• 
If you forget to take your pills in the evening, you can take your missed dose up to 6 hours after your normally scheduled time.  If it has been more than 6 
hours from the missed dose (i.e., less than 6 hours to your next scheduled dose), skip the dose and take the next scheduled dose at the next usual time 
(one dose only).  Please call your study nurse or doctor to discuss missed doses. 
• 
If you vomit your pills, write this down in your pill diary.  Do not take a replacement dose.    Take the next scheduled dose as usual (one dose only).  Please 
call your study nurse or doctor to discuss vomited doses. 
Additional Instructions: 
• 
You must avoid eating or drinking any foods with Seville oranges (like marmalade), grapefruit or foods or drink with grapefruit, and any exotic fruits 
during the entire treatment period. 
• 
You should drink 8 to 10 glasses of clear liquids a day for the entire treatment period.  
• 
Keep your study drug in the original container(s) at room temperature.  Keep study drug away from children, persons cannot read the label, and pets.   
• 
Do not throw away empty bottles, and do not throw the study drug in the trash or flush into the toilet.  
• 
Bring this diary, all pill bottles, and any unused pills to each clinic visit.  Your Treatment Team will collect your diary, all pill bottles and any unused study 
drug, and you will be given a new pill diary at that time.  
• 
Contact your study doctor or nurse if you are having any new or worsening side effects. Contact your study doctor or nurse as soon as possible if you are 
experiencing diarrhea.  
• 
Do not begin any new medication, over-the-counter drug, or herbal preparation without first checking with your study doctor or nurse to determine if it is 
acceptable to take while on this study.  
• 
Each cycle is 28 days of morning and evening pills.  If you start the cycle in the evening (P.M. dose), you may end the cycle in the morning of the 29th day. 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
104 
 
Each cycle is 28 days of morning and evening pills.  If you start the cycle in the evening (P.M. dose), you may end the cycle in the morning of the 29th day. 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date: 
            A.M. DOSE 
No. of pills: ________ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: __________ 
Time: ______________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials  
Date: 
A.M. DOSE 
No. of pills: ________ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: _______ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date: 
A.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date: 
A.M. DOSE 
No. of pills: __________ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: __________ 
Time: ______________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A. M. DOSE 
No. of pills: ________ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
105 
 
Each cycle is 28 days of morning and evening pills.  If you start the cycle in the evening (P.M. dose), you may end the cycle in the morning of the 29th day. 
Participant/Guardian Signature: _________________________________     Date: ________________ 
 
To be completed by study personnel:   
# of 50 mg Bottles Returned: ________           # of 50 mg Pills Returned: ________ 
 
Compare with drug diary entries made by participant or guardian.  If discrepancy (in the # of bottles or the # of pills returned), please reconcile: 
 
 
 
Study Personnel Signature: ______________________________ 
Date: ________________
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: ______________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
___________ 
Initials 
Day 29 
 
 
 
 
 
 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: 
_______ 
Time: ______________ 
 
___________ 
Initials 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
106 
 
APPENDIX F 
ABEMACICLIB DOSING INSTRUCTIONS & DRUG DIARY (Cohort 1 Pre-Surgery) 
To be completed by study personnel:     
Patient ID #_______  Patient Initials: ______  Pre-Surgery Cycle Month & Year: _________    Abemaciclib Dose: ______mg, two times a day.   
TAKE ____  pill(s) in the morning and ____ pill(s) in the evening.  
Abemaciclib Description: 
• 
Your study drug (Abemaciclib) is supplied as 50 mg mixture beige tablet. 
Abemaciclib Instructions – When and How: 
• 
Take study drug (Abemaciclib) twice a day, once in the morning and once in the evening.  
• 
Take the drugs at approximately the same time each morning and evening, so that you are taking the drugs 12 hours apart.  Morning and evening doses 
should be taken as close to a 7AM & 7PM schedule as possible (7 in the morning, 7 at night, 7 the next morning, and so on). 
• 
Take the pill(s) with a glass of water and swallow them whole; do not chew them or crush them. Abemaciclib can be taken with or without food. 
• 
Do not skip any doses. 
• 
If you forget to take your pills in the morning you can take your missed dose up to 6 hours after your normally scheduled time.  If it has been more than 6 
hours, skip the dose and take the next scheduled dose at the usual time in the evening (one dose only).  Please call your study nurse or doctor to discuss 
missed doses.  
• 
If you forget to take your pills in the evening, you can take your missed dose up to 6 hours after your normally scheduled time.  If it has been more than 6 
hours from the missed dose (i.e., less than 6 hours to your next scheduled dose), skip the dose and take the next scheduled dose at the next usual time 
(one dose only).  Please call your study nurse or doctor to discuss missed doses. 
• 
If you vomit your pills, write this down in your pill diary.  Do not take a replacement dose.    Take the next scheduled dose as usual (one dose only).  Please 
call your study nurse or doctor to discuss vomited doses. 
• 
On the day of surgery, you will be asked to take your morning dose at the hospital; therefore, please bring your pills with you. Do not take any further 
doses after surgery. Return any remaining pills to the study team.  
Additional Instructions: 
• 
You must avoid eating or drinking any foods with Seville oranges (like marmalade), grapefruit or foods or drink with grapefruit, and any exotic fruits 
during the entire treatment period. 
• 
You should drink 8 to 10 glasses of clear liquids a day for the entire treatment period.  
• 
Keep your study drug in the original container(s) at room temperature.  Keep study drug away from children, persons cannot read the label, and pets.   
• 
Do not throw away empty bottles, and do not throw the study drug in the trash or flush into the toilet.  
• 
Bring this diary, all pill bottles, and any unused pills to each clinic visit.  Your Treatment Team will collect your diary, all pill bottles and any unused study 
drug, and you will be given a new pill diary at that time.  
• 
Contact your study doctor or nurse if you are having any new or worsening side effects.  Contact your study doctor or nurse as soon as possible if you are 
experiencing diarrhea.  
• 
Do not begin any new medication, over-the-counter drug, or herbal preparation without first checking with your study doctor or nurse to determine if it is 
acceptable to take while on this study.  
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
107 
 
 
Please stop taking abemaciclib after on-study surgery until you are evaluated by the study team.  All unused study medication should be returned to the study team.   
 
Participant/Guardian Signature: _________________________________     Date: ________________ 
 
 
To be completed by study personnel:   
# of 50 mg Bottles Returned: ________           # of 50 mg Pills Returned: ________ 
 
Compare with drug diary entries made by participant or guardian.  If discrepancy (in the # of bottles or the # of pills returned), please reconcile: 
 
 
 
Study Personnel Signature: ______________________________ 
Date: ________________ 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date: 
            A.M. DOSE 
No. of pills: _______ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: __________ 
Time: ______________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: _______ 
 Time: ____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials  
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: _______ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date: 
A.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
P.M. DOSE 
No. of pills: _________ 
Time: ______________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M.DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
            A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: _________ 
Time: _____________ 
 
___________ 
Initials 
Date: 
            A.M. DOSE 
No. of pills: ________ 
Time: _____________ 
 
P.M. DOSE 
No. of pills: _________ 
Time: _____________ 
 
___________ 
Initials 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
108 
APPENDIX G 
MRI ACQUISITION PROTOCOL 
 
Brain MRI will be acquired at baseline  and every 8 weeks after treatment initiation as detailed in 
Section 10 Study Calendar.  All MRI exams will be performed based on standardized parameters 
recommended by the Jumpstarting Brain Tumor Drug Development Coalition Imaging 
Standardization Steering Committee  (Ellingson et al.  Neuro Oncol. 2015 Sep;17(9):1188-98). 
The following sequences are included: (i) parameter-matched precontrast and postcontrast 
inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-
weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1-
weighted images to control timing of images after contrast administration; (iii) precontrast, axial 
2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional 
diffusion-weighted images.   The T2-weighted sequence should be performed following contrast 
injection, before acquisition of T1-weighted post-contrast sequences.  The protocol can also 
include additional advanced imaging sequences such as perfusion weighted imaging (PWI) and 
susceptibility weighted imaging (SWI). Detailed parameters are listed in Table below.  
When possible, MRI exams should be done using the same MRI scanner for each subject.  If this 
is not achievable, patients should at the very least be scanned on MRI scanners with the same 
field strength (1.5T or 3T).  The chemical composition and dose of gadolinium contrast agents 
should also be the same for each patient during trial and should be explicitly documented on the 
MR system during acquisition or labeled in the DICOM header. 
 
Table: MRI Protocol 
1. Localizer 
2. Axial 3D T1w (IR-GRE)1 
3. Ax 2D FLAIR2 
4. Ax 2D SS-EPI DWI3 
5. Ax GRE or Ax SWI 
6. Contrast Injection 
7. Ax EPI Perfusion 
8. Ax 2D SE T2w4 
 
9. Axial 2D SE T1w 
10. Axial 3D T1w (IR-GRE)1  
Sequence 
 
TSEc SS-EPIg 
Contrast Injectiona 
TSEc IR-GREe,f 
Plane  
Axial Axial Axial Sagittal/axial 
Mode  
2D 
2D 
2D 
3D 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021

A Phase 0/2 Study of Abemaciclib in Recurrent Glioblastoma 
Version 4.0 – July 13, 2021 
109 
 
1. TR [ms] 
2100, TI [ms] 1100, Flip angle 10°–15°, Frequency ≥172, Phase ≥172, 
NEX ≥1, FOV 256 mm, Slice thickness ≤1.5 mm. Gap/spacing 0, Parallel imaging up to 
2x 
2. TR [ms] 
>6000, TE [ms], 
100–140, TI [ms] 2000–2500, Flip angle 90°/≥160°, 
Frequency ≥256, Phase ≥256, NEX ≥1, FOV 240 mm, Slice thickness ≤4 mm, 
Gap/spacing 0, Parallel imaging up to 2x 
3. TR [ms] 
>5000, TE [ms] , Flip angle 90°/180°, Frequency ≥128, Phase ≥128, NEX 
≥1, FOV 240 mm, Slice thickness ≤4 mm, Gap/spacing 0, Parallel imaging up to 2x, b = 
0, 500, 1000 s/mm2 ≥3 directions 
4. TR [ms] 
>2500, TE [ms], 
80–120, Flip angle 90°/≥160°, Frequency ≥256, 
Phase ≥256, NEX ≥1, FOV 240 mm, Slice thickness ≤4 mm, Gap/spacing 0, Parallel 
imaging up to 2x.  Post-contrast sequence (10) should be obtained within 8 minutes from 
time of contrast injection. 
 
 
Dana Farber
IRB NUMBER: 16-383
IRB APPROVAL DATE: 8/12/2021