Conditions: Breast Neoplasm Hormone Receptor Positive Breast Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This is a phase 2 single-arm, open-label determining efficacy of Neo-adjuvant Abemaciclib and Fulvestrant in subjects with Hormone receptor positive patients with localized non-metastatic breast cancer who develop local recurrence while on adjuvant endocrine therapy with molecular evidence of endocrine resistance.

Detailed description:

Arms:
arm 1: Abemaciclib will be administered orally at the dose of 150 mg twice daily. Fulvestrant will be administered intramuscularly at an initial loading dose of 500mg on days 1 and 15 of the first cycle and then 500 mg intramuscularly every first day of each subsequent cycle. One cycle is 28 days.

Interventions: intervention 1: Abemaciclib intervention 2: Fulvestrant
Intervention descriptions: intervention 1: Given PO intervention 2: Given Intramuscularly

Protocol document:
Prot_SAP_ICF_000.pdf: 
Protocol #: UCI 18-79 
MP 09/09/2020 
 
 
 
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UCI 18-79 
A Phase II Open Label Trial of Neoadjuvant Abemaciclib with Fulvestrant in Patients who Develop 
Localized Recurrence while on Adjuvant Endocrine Therapy with Molecular Evidence of Endocrine 
Resistance  
 
 
 
Principal Investigator:  
Ritesh Parajuli, MD 
 
 
 
 
University of California Irvine/Division of Hematology/Oncology 
 
 
 
 
101 The City Dr. South, Orange, CA 92868 
 
 
 
 
(Phone) 714-456-8614  
 
 
 
 
Email rparajul@hs.uci.edu 
 
 
 
 
Breast Oncology 
 
Sub-Investigator(s): 
 
Rita Mehta, MD 
 
 
 
 
Paul Coluzzi, MD 
 
 
 
 
Andrea Nanci, M 
 
 
 
 
Khosrow Mahdavi, MD 
 
 
 
 
Department of Medicine/Division of Hematology/Oncology 
 
 
 
 
 
 
 
 
 
John Butler, MD 
 
 
 
 
Karen Lane, MD 
 
 
 
 
Kari Kansal, MD 
 
 
 
 
Erin Lin, MD 
 
 
 
 
Department of Medicine/Division of Surgical Oncology 
 
Biostatistician: 
 
Argyrio Ziogas, MD 
 
 
 
 
Principal Statistician 
 
 
 
 
University of California, Irvine 
 
 
 
 
222D Irvine Hall, Irvine, CA 92697 
 
 
 
 
(Phone) 949-824-1587 
 
 
 
 
Email aziogas@hs.uci.edu 
 
 
 
 
 
 
Coordinating Center:                UC Irvine Chao Family Comprehensive Cancer Center 
             101 The City Drive South, Orange CA 92868 
             Contact: Nidhisha Patel, Clinical Research Manager 
             Phone: 714-509-2430 
             Email: uci1879@hs.uci.edu 
 
Funding Source:  
Eli Lilly Pharmaceuticals 
 
How is the Agent Supplied?: Eli Lilly Pharmaceuticals 
  
Current version 
 
 09/09/2020 
 
Previous version(s): 
 
03/10/2020 
 
 
 
 
11/18/2019  
 
 
 
 
 


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The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of ContentsUCI 18-79 1 
LIST OF ABBREVIATIONS ........................................................................................................ 5 
STUDY SCHEMA ......................................................................................................................... 6 
STUDY SUMMARY ..................................................................................................................... 6 
1.0 
BACKGROUND AND RATIONALE ............................................................................... 9 
1.1 
Disease Background ..................................................................................................... 9 
1.2 
Study Agent(s) Background and Associated Known Toxicities ........................... 10 
1.3 
Other Agents ................................................................................................................ 10 
1.4 
Rationale ....................................................................................................................... 10 
1.5 
Correlative Studies ...................................................................................................... 12 
2.0 
STUDY OBJECTIVES .................................................................................................... 13 
2.1 
Primary Objectives ...................................................................................................... 13 
2.2 
Secondary Objectives ................................................................................................. 13 
2.3 
Correlative Objectives ................................................................................................. 13 
2.4 
Endpoints ...................................................................................................................... 13 
3.0 
PATIENT ELIGIBILITY ................................................................................................... 13 
3.1 
Inclusion Criteria .......................................................................................................... 14 
3.2 
Exclusion Criteria ......................................................................................................... 15 
4.0 
TREATMENT PLAN........................................................................................................ 16 
4.1 
Treatment Dosage and Administration .................................................................... 16 
4.2 
Toxicities and Dosing Delays/Dose Modifications .................................................. 17 
4.3 
Fulvestrant Dose Modification and Management ................................................... 20 
4.4 
Concomitant Medications/Treatments ...................................................................... 20 
4.5 
Duration of Therapy .................................................................................................... 22 
4.6 
Duration of Follow Up ................................................................................................. 22 
4.7 
Removal of Patients from Protocol Therapy ........................................................... 22 
4.8 
Patient Replacement ................................................................................................... 22 
5.0 
STUDY PROCEDURES ................................................................................................. 22 
5.1 
Screening/Baseline Procedures ................................................................................ 22 
5.2 
Registration Procedures ............................................................................................. 24 
5.3 
Procedures During Treatment ................................................................................... 24 
5.4 
Follow-up Procedures ................................................................................................. 24 
5.5 
Time and Events Table ............................................................................................... 24 
5.6 
Removal of Subjects from Study ............................................................................... 26 
6.0 
Measurement of Effect ................................................................................................... 26 
6.1 
Pathologic Complete Response (pCR) .................................................................... 26 
6.2 
Antitumor Effect- Solid Tumors ................................................................................. 26 
6.3 
Safety/tolerability ......................................................................................................... 30 
7.0 
ADVERSE EVENTS ....................................................................................................... 30 
7.1 
Definitions ..................................................................................................................... 31 
7.2 
Steps to Determine If an Adverse Event Requires Expedited Reporting ........... 34 
7.3 
Reporting Requirements for Adverse Events .......................................................... 35 
7.4 
Additional Reporting Requirements to CFCCC DSMB and Lead  
7.5 
Additional Clinical Reporting Requirements to Eli Lilly Pharmaceuticals ........... 38 


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8.0 
DRUG INFORMATION ................................................................................................... 38 
8.1 
Abemaciclib .................................................................................................................. 38 
8.3 
Agent Accountability .................................................................................................... 40 
9.0 
CORRELATIVE STUDY ................................................................................................. 41 
10.0 STATISTICAL CONSIDERATIONS ............................................................................. 41 
10.1 Study Design ................................................................................................................ 42 
10.2 Sample Size and Accrual and Data Analyses Plans ............................................. 42 
11.0 STUDY MANAGEMENT ................................................................................................ 44 
11.1 Conflict of Interest ........................................................................................................ 44 
11.2 Institutional Review Board (IRB) Approval and Consent ...................................... 44 
11.2 Data Completion .......................................................................................................... 44 
11.3 Data and Safety Monitoring/Auditing ........................................................................ 45  
11.4 Protocol Deviation ....................................................................................................... 45 
11.5 Amendments to the Protocol ..................................................................................... 45 
11.6 Record Retention ......................................................................................................... 46 
11.7 Obligations of Investigators ........................................................................................ 46 
12.0 REFERENCES ................................................................................................................ 46 
13.0 APPENDICES .................................................................................................................. 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ER 
Estrogen Receptor 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
ILD 
Interstitial Lung Disease  
IM 
Intramuscularly 
MBC 
Metastatic Breast Cancer 
MTD 
Maximum Tolerated Dose 
NGS 
Next Generation Sequencing 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCP 
Primary Care Physician 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PI 
Principal Investigator 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
PRBC 
Packed Red Blood Cells 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 


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STUDY SCHEMA 
 
STUDY SUMMARY 
Title 
A Phase II Open Label Trial of Neoadjuvant Abemaciclib with Fulvestrant 
in Patients who Develop Localized Recurrence while on Adjuvant 
Endocrine Therapy with Molecular Evidence of Endocrine Resistance 
Protocol Number 
UCI 18-79 
Phase 
Phase 2 
Methodology 
Open-Label 
Study Duration 
5 years 
Study Center(s) 
Single-Center 
 


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Objectives 
Primary Objective: 
To determine if Neo-adjuvant Abemaciclib and Fulvestrant improves a 
pathological complete response (pCR) in patients with Hormone 
Receptor positive patients with localized non-metastatic breast cancer 
who develop local recurrence while on adjuvant endocrine therapy with 
molecular evidence of endocrine resistance 
 
Secondary Objectives: 
1. To determine the objective response rate (ORR) in the breast 
and/or the axillary lymph nodes 
2. To determine if the combination of Abemaciclib and Fulvestrant 
increases the percentage of patients who undergo breast 
conserving surgery 
3. Recurrence disease-free survival 
4. Safety and Toxicity 
5. To determine the percentage change in the Ki 67 from baseline 
to the treated specimen after breast surgery 
6. To determine the preoperative endocrine prognostic index (PEPI) 
score as predictors of response to Neo-adjuvant Abemaciclib and 
Fulvestrant 
 
Correlative Objectives: 
1. To determine if genomic analysis of patient matched breast 
tissue samples and serial mutational tracking of circulating tumor 
DNA can identify new mechanisms of endocrine resistance and 
how Abemaciclib overcomes endocrine resistance 
2. To determine the mechanism of response or resistance to 
Abemaciclib 
3. To determine biomarkers related to the Rb pathway 
Number of Subjects 
30 
Diagnosis and Main 
Inclusion Criteria 
Inclusion Criteria 
1. Post-menopausal female patients who have given written 
informed consent 
2. Histologically confirmed ER+ Breast Cancer 
3. Patients must have localized non-metastatic breast cancer 
4. Patients must have localized recurrence while on adjuvant 
endocrine therapy 
5. Patients must have molecular evidence of endocrine resistance 
6. ECOG performance 0-2 and adequate organ function 
 
Exclusion Criteria 
1. Stage IV Metastatic Breast Cancer will be excluded 
2. Patients with Her-2 positive and triple negative breast cancer will 
be excluded 
3. Inflammatory breast cancer 
4. Patients must have developed localized recurrence while on 
adjuvant endocrine therapy and hence newly diagnosed 
endocrine therapy naïve patients will be excluded 
5. Patients without molecular evidence of endocrine resistance will 
be excluded 
6. Prior treatment with any CDK 4/6 inhibitor and/or Fulvestrant will 
be excluded 


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Study Product(s), Dose, 
Route, Regimen 
Abemaciclib 150mg twice daily administered orally in combination with 
Fulvestrant administered intramuscularly. The initial loading dose of 
Fulvestrant is 500mg on D1 and D15 of first cycle and then 500mg 
intramuscularly at D1 of each subsequent cycle (each cycle is 28 days). 
This combination therapy will continue until maximum response is 
obtained or patients develop unacceptable toxicity. Following therapy 
phase, patients will undergo definitive surgical treatment. 
Duration of administration 
The study will consist of a screening period of up to 28 days, a treatment 
period until maximum response per investigator discretion based on 
clinical and radiographic assessments, or until disease progression or 
unacceptable toxicity. The treatment phase will be followed by surgery, 
and follow up every 6 months until death or end of study at five years 
(whichever occurs first). 
Statistical Methodology 
Efficacy of the study will be measured by estimating the objective 
response rate (CR, PR) in the breast and/or the axillary lymph nodes or 
determining if the combination of Abemaciclib and Fulvestrant increases 
the percentage of patients who undergo breast conserving surgery. The 
latter will be measured by constructing 95% CI. We plan to use survival 
analysis methods such as Kaplan-Meier estimates of survival probability 
for univariate analysis and log rank tests in order to evaluate differences 
among distinct patient characteristics such as age group for recurrence 
or disease-free survival. For multivariate analysis we plan to use the Cox 
proportional hazards model in order to examine survival adjusted for a 
number of covariates. Safety and toxicity will be examined by the 
incidence of treatment-emergent, treatment-related adverse events 
(TRAEs), and serious adverse events (SAE). Consequently, side effects 
and adherence to the protocol will be closely monitored throughout the 
duration of the study. Interim analyses will be performed to assess the 
side effects. Contingency tables will be constructed to compare the 
proportion of patients with side effects by study characteristics (e.g. age, 
race ethnicity and other clinical and epidemiologic characteristics). 
Distributions of all data items will be generated and examined for the 
presence of outliers. This will be to assess the general form of the 
distributions, and to compute measures of central tendency and 
variability. Trellis graphics will be used for data display including 
histograms, boxplots, and Q-Q normal plots. In addition, we plan to 
examine if genomic analysis of patient-matched breast tissue samples 
and serial mutational tracking of circulating tumor DNA can identify new 
mechanisms of endocrine resistance and the way Abemaciclib 
overcomes this resistance. For the analyses of matched pair tissue data, 
we will use paired t tests or Wilcoxon sign rank statistical analysis in 
order to test differences in recurrent and treated breast tissue. We plan 
to measure absolute values and changes in circulating tumor DNA and 
correlate them with endocrine resistance. If serial monitoring of ctDNA 
can provide markers of resistance, we will quantify endocrine resistance 
as a composite outcome that will be computed as dichotomous variable 
if it happens (yes or no) and at what time interval during the study. We 
will start by using frequency table analysis to examine the relationship 
between resistance or sensitivity and specific mutations. 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Breast cancer is one of the most common cancers in women. In 2012, there were 
approximately1.7 million new cases of breast cancer worldwide; since 2008, the 
worldwide incidence of breast cancer has increased by more than 20% and mortality has 
increased by 14% (Bray et al. 2013; Ferlay et al. 2013). While early stage disease is 
treatable, patients with metastatic breast cancer (mBC) have a median overall survival 
(OS) of only 2 to 3 years (Cardoso et al. 2012). The treatment for women diagnosed with 
hormone receptor positive (HR+) mBC includes endocrine therapy. In postmenopausal 
women, aromatase inhibitors (including anastrozole and letrozole) are recommended for 
the initial treatment of mBC, if not used in the adjuvant setting or if discontinued for at 
least 12 months (Cardoso et al. 2012). However, de novo or acquired resistance to 
adjuvant endocrine therapy and metastatic breast cancer remains an important clinical 
challenge. 
 
CDK 4/6 Inhibitors in Metastatic Breast Cancer 
Resistance to endocrine therapy in patients with HR+ Metastatic breast cancer is a major 
cause of treatment failure. Over activation of the Cyclin Dependent Kinase (CDK) 
pathway is an important mechanism of endocrine resistance. Cyclin D1 interacts with 
cyclin-dependent kinases 
4 and 6 (hereafter CDK4 and CDK6) in an active protein complex that promotes cell 
proliferation (Velasco-Velazquez et al. 2011). Many HR+ breast cancers demonstrate an 
intact retinoblastoma tumor suppressive function, however, overexpression of cyclin D1 
protein by oncogenic signaling occurs in approximately 30% to 50% of cancers. Cyclin 
D1 is regarded as the most frequently overexpressed gene in primary breast cancer, with 
amplification of the encoding gene, CCND1, occurring in approximately 15% of breast 
cancers (Casimiro et al. 2014). Therefore, CDK4 and CDK6 represent a potential 
therapeutic target for  HR+ breast cancer. During the cell cycle, the G1 restriction point 
controls entry into S phase and is essential for proper regulation of cell proliferation 
(Sherr 1996; Ortega et al. 2002). CDK4 and CDK6 participate in a complex with the D-
type cyclins to initiate progression through the G1 restriction point. The CDK4 and CDK6 
- cyclin D1 complex regulates the G1 restriction point through phosphorylation and 
inactivation of the retinoblastoma (Rb) tumor suppressor protein, thereby promoting S 
phase entry. Alterations in this pathway occur frequently in human cancers and involve: 
1) loss of functional CDK inhibitors through deletion or epigenetic silencing; 2) activating 
mutations and/or overexpression of CDK4 and CDK6 or the D-type cyclins; and 3) loss of 
functional Rb through mutation or deletion. Except for tumors with functional loss of Rb, 
which functions downstream of the CDK4 and CDK6 - cyclin D1 complex, most cancers 
are potentially sensitive to pharmacologic inhibition of CDK4 and CDK6. From a 
therapeutic standpoint, the goal of inhibiting CDK4 and CDK6 with a small molecule is to 
prevent cell cycle progression through the G1 restriction point, thus arresting tumor 
growth. Among postmenopausal women with hormone receptor-positive metastatic 
breast cancer,  combinations of the AI letrozole with CDK 4/6 inhibitors (palbociclib, 
ribociclib, or abemaciclib) have demonstrated improved progression-free survival (PFS) 
relative to letrozole alone and have been approved by the US Food and Drug 
Administration (FDA) in this setting.. 


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1.2 
Study Agent(s) Background and Associated Known Toxicities 
Abemaciclib is a selective and potent small molecule inhibitor of CDK4 and CDK 6. 
Abemaciclib is FDA approved in combination with an AI for the initial treatment of 
postmenopausal women with hormone receptor-positive, HER2-negative breast cancer. 
In the MONARCH 3 trial, the combination of abemaciclib with an AI (letrozole or 
anastrozole) was compared with AI monotherapy for the frontline treatment of women 
with advanced hormone receptor-positive, HER2-negative breast cancer. PFS, the 
primary endpoint of the trial, was increased with the combination compared with an AI 
alone (median not reached versus 14.7 months, respectively. Abemaciclib has been 
shown to combine effectively with fulvestrant. In the MONARCH 2 phase III trial, 669 
patients who had progressed while receiving ET were randomly assigned to fulvestrant 
with or without the CDK 4/6-inhibitor abemaciclib. Those receiving abemaciclib 
experienced an improved PFS relative to those receiving fulvestrant  alone (16.4 versus 
9.3 months; HR 0.55, 95% CI 0.45-0.68). The ORR was higher in those receiving 
abemaciclib (48 versus 21 percent). The FDA in combination approves Abemaciclib with 
fulvestrant for women with progressive disease after prior endocrine therapy. Results 
from the phase II MONARCH 1 study, which enrolled 132 patients with a median of three 
prior lines of treatment (including one or two prior chemotherapy regimens in the 
metastatic setting), single- agent treatment with the novel CDK 4/6 inhibitor abemaciclib 
induced tumor response in 20 percent of patients, with a clinical benefit rate (stable or 
responding disease) of 42 percent, and median PFS of 6.0 months. The FDA has also 
approved abemaciclib as monotherapy for women with progressive disease after 
endocrine therapy and chemotherapy. 
1.3 
Other Agents 
Fulvestrant is an ER antagonist that blocks ER dimerization and DNA binding, increases 
ER turnover, and inhibits nuclear uptake of the receptor. Fulvestrant has been approved 
in combination with either Palbociclib or Ribociclib or Abemacilcib in the treatment of 
patients with ER+ metastatic breast cancer. 
1.4 
Rationale 
Neoadjuvant Endocrine Therapy: 
 
Neo-adjuvant chemotherapy (NACT) refers to systemic treatment of breast cancer prior 
to definite surgical treatment. While all systemic therapy given for non-metastatic invasive 
breast cancer is intended to reduce the risk of distant recurrence, the purpose of 
administering it neoadjuvantly is to downstage the tumor, allow for less extensive 
surgery, improve cosmetic outcomes and reduce postoperative complications (1). By 
reducing the size of the primary tumor, preoperative therapy also allows for higher rate of 
breast conserving surgery. Achieving a complete pathologic response to Neo-Adjuvant 
chemotherapy has prognostic implications in patients with breast cancer (2, 3) and failure 
to achieve a complete pathologic response are associated with a high risk of local 
relapse.  
 
Unlike Her-2+ and Triple negative breast cancers, HR+ breast cancers are less likely to 
respond to NACT (4-8). Chemotherapy can shrink HR+ tumors and facilitate better 
surgical outcomes, but is less likely to achieve a complete pCR in HR+ cancers, 
especially luminal A cancers than for more proliferative histology (9, 10). While 
historically neoadjuvant endocrine therapy (NET) has been reserved for patients with 
substantial comorbid health problems who would not tolerate chemotherapy, it is coming 
to be seen as a viable alternative for other patients, especially those with strong HR+ 
tumors that are strongly ER+. Tumors that are more likely to respond to NET have strong 


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HR expression (≥ 50% ER+ or an Allred score of 7 or 8) and a low proliferative index (Ki 
67 < 10 or 15 %). 
 
The standard of care options for Post-menopausal patient who develop localized or 
locally advanced recurrent HR+ Breast cancer while on adjuvant endocrine therapy 
remains to be surgical resection. The treatment depends on the type of local treatment 
they received at the initial diagnosis. Recurrence can happen after a lumpectomy and 
radiation or following mastectomy. Mastectomy is the surgical standard of care for most 
patients with a local recurrence following breast conserving surgery and radiation. 
Surgery in the form of wide local excision is recommended for post mastectomy chest 
wall recurrence. The role of radiation in the management of localized recurrence also 
depends upon if patients received adjuvant radiation at the initial diagnosis. Surgery and 
radiation in recurrent HR + breast cancer only address local control. Patients with 
recurrent breast cancer are at risk of developing metastatic breast cancer, have 
microscopic metastasis and many have evidence of endocrine resistance. Furthermore, 
extensive loco-regional recurrence is not amenable to surgical resection alone. Surgery 
and radiation does not address endocrine resistance nor does it treat microscopic 
metastasis. Hence, addressing endocrine resistance as well as adopting a targeted Neo-
Adjuvant approach based on patient’s tumor profiling and then treating them with the 
Abemaciclib and Fulvestrant to downstage the tumor, limit chemotherapy induced toxicity 
is the next logical step in the management of patients. These patients often land up 
getting Neo-Adjuvant chemotherapy. Few achieve a complete pathologic response and 
many are subjected to severe peri-operative complications. Hence, there continues to be 
an unmet medical need to develop alternate therapies that are less toxic and provide 
better outcomes. Neoadjuvant endocrine therapy can be an alternative option to 
chemotherapy in Hormone Receptor positive (HR+) tumors, particularly for 
postmenopausal women. Unlike in premenopausal women, available data suggest that 
NET is associated with similar response rates and rates of breast- conserving surgery 
(BCS) as NACT with lower toxicity, although survival data with NET are not yet available 
(11-15). 
 
Resistance to endocrine therapy in patients with HR+ Metastatic breast cancer is a major 
cause of treatment failure. Cyclin-dependent kinases 4 and 6 (CDK 4 and 6) inhibition is 
proving to be an effective strategy in overcoming endocrine resistance. The data on the 
use of CDK 4/6 inhibitors with Fulvestrant or an Aromatase Inhibitor has been discussed 
in section 1.1 and 1.2. However, patients will eventually become resistant to CDK 4/6 
inhibitors. Other than ER positivity, we do not fully understand the mechanism of 
sensitivity or resistance to CDK 4/6 inhibitors in ER+ MBC apart from Rb (Retinoblastoma 
gene) loss predicting for resistance. However, rather than waiting for endocrine 
resistance to develop in the adjuvant or the metastatic setting, identifying and targeting 
endocrine resistance in the Neo-adjuvant setting is expected to delay or prevent the 
development of endocrine resistance and hence improve patient outcomes. The concept 
for this proposal originated from real patient scenarios. We identified three patients in our 
institution that developed localized non-metastatic HR+ recurrent breast cancer while on 
adjuvant Anastrozole. 
 
All three were treated with NACT and none achieved a complete pCR. Molecular analysis 
of the recurrent tissue harbored CCND1 amplification and ctDNA analysis showed ESR1 
mutations in all of the three patients. Besides Estrogen receptor positivity, CCND1 
amplification is one suggested biomarker that could predict response to CDK 4/6 
inhibitors. Furthermore, the PALOMA studies showed that Fulvestrant is effective in 
patients with ESR1 mutation. We then hypothesized this cohort of patients with the 


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aforementioned genomic changes will benefit from a combination of a CDK 4/6 inhibitor 
and Fulvestrant. 
 
Several ongoing trials are investigating the role of combination therapy including the 
combination of AIs with CDK 4/6 inhibitors (NeoMONARCH), PI3K inhibitors (LORELEI) 
and dual endocrine therapy (ALTERNATE).The NeoMONARCH study randomly assigned 
postmenopausal women with early stage HR+ breast cancer to Neoadjuvant therapy with 
Anastrozole, Abemaciclib or Anastrozole with Abemacilib. The study met its primary 
endpoint by showing that Ki-67 levels were significantly reduced in breast cancer cells 
from the 107 patients who received abemaciclib, either alone or in combination with 
anastrozole, compared with the 54 patients who received anastrozole only. Treatment 
with abemaciclib plus anastrozole led to a reduction in tumor size in most patients, as 
assessed by clinical and radiologic evaluation. This clearly showed that Abemaciclib 
works in the Neo-Adjuvant setting. While both CDK 4/6 inhibitors and Fulvestrant have 
been known to overcome endocrine resistance, a combination of Abemaciclib with 
Fulvestrant ( as proposed in this trial) is expected to yield higher response rates, 
reduction in the ki-67 index and lead onto an improved pathologic complete response. 
 
None of the clinical trials evaluating the combination of Neoadjuvant endocrine therapy 
with a CDK 4/6 inhibitor has addressed the unique cohort and the biology of endocrine 
resistance in such patients that is being proposed in this study. Identifying endocrine 
resistance in the Neo-adjuvant manner and targeting to improve patient outcomes is the 
fundamental goal of our study. Therefore, based on a clear unmet medical need, we plan 
to conduct a prospective, open-label Phase II study of Neo-Adjuvant Abemaciclib with 
Fulvestrant in post-menopausal patients who develop localized HR+ non-metastatic 
recurrence while on adjuvant endocrine therapy but with molecular evidence of endocrine 
resistance and longitudinally monitor ctDNA for evolving mutations. This personalized 
and targeted Neoadjuvant approach has the potential to demonstrate that Abemaciclib 
and Fulvestrant can increase pCR, reveal mechanisms of endocrine resistance and 
elucidate biomarkers of response or resistance to Abemaciclib. To the best of our 
knowledge, a study like this has not yet been conducted. 
 
Potential Risk of Delaying Surgical Intervention: 
 
The subjects enrolled in this trial will be treated with Abemaciclib and Fulvestrant until 
maximal response is obtained or until patients can tolerate it, following which they will 
undergo surgical resection with a curative intent. At any point in the study, if patients 
have signs and symptoms of metastasis, they will undergo systemic scans to seek for 
metastatic sites. Patients will be undergoing systemic scans to rule out metastasis prior 
to enrollment in the study. There remains a risk of disease progression while surgery is 
being delayed. However, Abemaciclib and Fulvestrant has currently been approved for 
the treatment of metastatic ER+ breast cancer now. We believe that patients will have a 
relatively lower risk of disease progression while on this treatment since this regimen is 
standard of care in treating ER+ MBC and also since patients will undergo systemic 
scans prior to enrollment. Furthermore, the risk of delaying surgical intervention will be 
described in the informed consent provided to research participants. 
1.5 
Correlative Studies 
 
 
Molecular analysis in the form of Next Generation Sequencing will be done on the 
treatment naïve archival breast tissue, on the breast tissue at the time of recurrence and 
on the surgical specimen. Blood will be collected as well for analysis of ctDNA before 
enrollment, every 3 months while on treatment and then every 6 months (after definitive 
surgery) until the end of the study at five years. The molecular analysis by Next 


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generation sequencing (NGS) will be done by Tempus using their standard platform. No 
identifiable information for the correlative studies will be sent to Tempus. Only subject ID 
and study site information will be provided on requisition forms, kit labels, and any reports 
(e.g. pathology report, progress note) are being submitted to Tempus.   
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To determine if Neo-adjuvant Abemaciclib and Fulvestrant improves a 
pathological complete response in patients with Hormone Receptor positive 
patients with localized non- metastatic breast cancer who develop local 
recurrence while on adjuvant endocrine therapy with molecular evidence of 
endocrine resistance 
2.2 
Secondary Objectives  
2.2.1 
To determine the objective response rate (ORR) in the breast and/or the axillary 
lymph nodes 
 
2.2.2 
To determine if the combination of Abemaciclib and Fulvestrant increases the 
percentage of patients who undergo breast conserving surgery 
 
2.2.3 
Recurrence disease-free survival 
 
2.2.4  
Safety and Toxicity 
 
2.2.5     To determine the percentage change in the Ki 67 from baseline to the treated 
specimen after breast surgery 
 
2.2.6     To determine the preoperative endocrine prognostic index (PEPI) score as 
predictors of response to Neo-adjuvant Abemaciclib and Fulvestrant 
  
2.3 
Correlative Objectives 
2.3.1 
To determine if genomic analysis of patient matched breast tissue samples and 
serial mutational tracking of circulating tumor DNA can identify new mechanisms 
of endocrine resistance and how Abemaciclib overcomes endocrine resistance 
 
2.3.2    To determine the mechanism of response or resistance to Abemaciclib  
 
2.3.3    To determine biomarkers related to the Rb pathway 
2.4 
Endpoints 
 
The primary endpoint is pathological complete response (pCR) as defined by no 
evidence of tumor cells in the final surgical specimen 
The secondary endpoints are ORR per RECIST 1.1 criteria, recurrence disease-free and 
incidence of AEs 
3.0 
PATIENT ELIGIBILITY 


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Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
3.1.1 
Patients must have a diagnosis of HR+ breast cancer. To fulfill the requirement of 
HR+ disease, a breast cancer must express, by immunohistochemistry (IHC), at 
least one of the hormone receptors (ER, progesterone receptor [PgR]) as defined 
in the relevant American Society of Clinical Oncology (ASCO)/College of 
American Pathologists (CAP) Guidelines (Hammond et al. 2010):  
 
For ER and PgR assays to be considered positive, ≥1% of tumor cell 
nuclei must be immunoreactive by immunohistochemistry (IHC) 
(Hammond et al. 2010). 
 
 
3.1.2     Patients must have Loco regional breast cancer (Stage I, Stage II and stage III 
per AJCC 8th edition criteria for staging of breast cancer) 
 
 
3.1.3 
Patients must have localized recurrence while on adjuvant endocrine therapy  
3.1.4 
Patients must have any known molecular evidence of endocrine resistance by 
next generation sequencing 
 
3.1.5     Age ≥ 18 years.  
 
 
3.1.6   ECOG performance status 0-1 
 
 
3.1.7 
Have post-menopausal status as defined by following: 
 
Prior bilateral oophorectomy 
 
Age ≥ 60 years 
 
Age < 60 and amenorrheic (non-treatment-induced amenorrhea 
secondary to tamoxifen, toremifene, ovarian suppression, or 
chemotherapy) for at least 12 months. Follicle-stimulating hormone 
(FSH) and estradiol must be in the postmenopausal range.  
 
 
 
3.1.8  
Have at least one measurable disease as defined per RECIST 1.1  
 
       
 
3.1.9   Adequate organ and marrow function as defined below: 
- Hemoglobin* 
 
> 8 g/dL 
- Absolute neutrophil count ≥ 1,500/mcL 
- Platelets  
 
≥ 100,000/mcl 
- Total bilirubin 
 
≤ 1.5 X institutional ULN  
Patients with Gilbert’s syndrome with a total bilirubin ≤2.0 times ULN and 
direct bilirubin within normal limits are permitted 
- AST (SGOT)/ALT (SPGT) ≤ 2.5 X institutional ULN 
      - Creatinine 
 
≤ 1.5 X institutional ULN   
 
*Patients may receive transfusion of packed red blood cells (PRBC) to 
achieve this hemoglobin level at the discretion of the investigator; however, 
initial study drug treatment must not begin earlier than the day after the 
PRBC transfusion. 


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3.1.10 Able to swallow oral medications 
 
3.1.11   Patients who received adjuvant radiotherapy must have completed and fully 
recovered from the acute effects of radiotherapy. A washout period of at least 14 
days is required between end of radiotherapy and screening for the study. 
 
3.1.12 Patients who received chemotherapy must have recovered (Common 
Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute 
effects of chemotherapy except for residual alopecia or Grade 2 peripheral 
neuropathy prior to enrollment. A washout period of at least 21 days is required 
between last chemotherapy dose and enrollment (provided the patient did not 
receive radiotherapy). 
3.1.13 Any known markers of response or resistance to CDK 4/6 inhibitors to be present 
in the biopsy specimen 
 
 
                          3.1.14  If patients have been treated with prior Neo-Adjuvant chemotherapy at the time 
of primary diagnosis and not at the time of recurrence, they will be included in the 
study. 
3.1.15 Must be able to sign a written informed consent, are reliable, willing to be 
available for the duration of the study and are willing to follow study procedures 
3.2 
Exclusion Criteria 
 
3.2.1 
Stage IV metastatic breast cancer 
 
This study will utilize the American Joint Committee on Cancer 
(AJCC) staging system, eight edition that provides a strategy for 
grouping patients with respect to prognosis. The AJCC has 
designated staging by TNM classification. The researchers will also 
review tumor size, lymph node status, and estrogen-receptor and 
progesterone-receptor levels in the tumor tissue. 
 
3.2.2 
Patients with HER2 positive and triple negative breast cancer 
 
To fulfill the requirement of HER2- and Triple negative disease, a 
breast cancer must not demonstrate, at initial diagnosis or upon 
subsequent biopsy, overexpression of HER2 or should not express 
ER or PR receptors by either IHC or in-situ hybridization (ISH) as 
defined in the relevant ASCO/CAP guidelines (Wolff et al. 2013). 
 
3.2.3 
Inflammatory breast cancer 
 
3.2.4 
Newly diagnosed endocrine naïve patients 
 
3.2.5 
No molecular evidence of endocrine resistance 
 
3.2.6 
Prior treatment with any CDK 4/6 inhibitor and/or Fulvestrant   
 
3.2.7 
Pre-menopausal women 
 
3.2.8 
Are currently receiving an investigational drug in a clinical trial or participating in 
any other type of medical research judged not to be scientifically or medically 


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compatible with this study. If a patient is currently enrolled in a clinical trial 
involving non-approved use of a device, then agreement with the principal 
investigator is required to establish eligibility  
 
3.2.9 
Have had major surgery within 14 days prior to enrollment to allow for post-
operative healing of the surgical wound  
 
3.2.10 Have initiated bisphosphonates or approved RANK ligand therapy for breast 
cancer with osseous metastasis, if patients are received Zolendronic acid or 
Denosumab  in  the adjuvant manner then such patients will be allowed 
participate  
 
3.2.11 Have serious preexisting medical conditions that, in the judgment of  the 
investigator, would preclude participation in this study (for example, history of 
major surgical resection involving the stomach or small bowel or preexisting 
Crohn’s disease or ulcerative colitis , interstitial lung disease, severe dyspnea at 
rest, any pre-existing chronic condition resulting in baseline grade 2 or higher 
diarrhea) 
 
3.2.12 Have a personal history of any of the following conditions: syncope or 
cardiovascular etiology, ventricular tachycardia, ventricular fibrillation or sudden 
cardiac arrest  
 
3.2.13 Have a history of any other cancer (except for non-melanoma skin cancer or 
carcinoma in situ of the cervix) unless in complete remission with no therapy for a 
minimum of three years or have received an autologous or allogeneic stem-cell 
transplant  
 
3.2.14 Have an active bacterial or fungal infection or a detectable viral infection (for 
example HIV or viral hepatitis). Screening is not required for enrollment 
 
3.2.15 Recent therapy with a biologic agent or a monoclonal therapy is excluded. Wash 
out of at least three half-lives of monoclonal antibody would be required to be 
enrolled. 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
4.1.1 
Abemaciclib will be administered orally at the dose of 150 mg twice daily. 
Fulvestrant will be administered intramuscularly at an initial loading dose of 
500mg on days 1 and 15 of the first cycle and then 500 mg intramuscularly every 
first day of each subsequent cycle. One cycle is 28 days. 
 
 
REGIMEN DESCRIPTION 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  


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Abemaciclib 
150 mg 
Oral (PO) 
BID 
4 
weeks 
(28 days) 
 
Fulvestrant 
500 mg 
IM  
C1D1, 
C1D15, and 
D1 of each 
subsequent 
cycle  
 
4.1.2 
Supportive Care Guidelines 
 
 
Necessary supportive measures for optimal medical care will be given throughout 
the study including antidiarrheal, blood components etc. Additional care will be 
administered as indicated by the treating physician and the subject’s medical 
need. All the concomitant medications and supportive therapy administered 
during the 30 days prior to the first dose until 30 days after the last dose must be 
recorded in OnCore eCRF. 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table (Section 5.4). Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 5.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
4.2.1 Abemaciclib Dose Modification and Management 
 
 
Please refer to the following tables for dose modifications for adverse reactions related to 
abemaciclib. If dose reduction is necessary, decrease the dose by 50 mg at a time. Discontinue 
abemaciclib for patients unable to tolerate 50 mg twice a day (BID). 
 
Abemaciclib Dose Modifications for Adverse Events 
 
Dose Level 
Abemaciclib dose in combination with 
fulvestrant 
Recommended Starting Dose 
150 mg 
First Dose Reduction 
100 mg 
Second Dose Reduction 
50 mg 
Third Dose Reduction 
Not applicable 
 
Hematologic Toxicities 
 
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. 
 
Hematologic Toxicity Dose Management Guidelines 
 
Monitor complete blood counts prior to the start of abemaciclib therapy, every 2 


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weeks for the first 2 months, monthly for the next 2 months, and as clinically 
indicated. 
 
CTCAE Grade 
Action 
Grade 1-2 
No dose modification required  
Grade 3 
Suspend dose until toxicity resolves to ≤Grade 
2. 
Dose reduction is not required. 
Grade 3, recurrent, or Grade 4 
Suspend dose until toxicity resolves to ≤Grade 
2. 
Resume at next lower dose. 
 
If blood cell growth factors are required, 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 at next lower dose unless 
already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current 
treatment guidelines. 
 
Hepatic Toxicities 
 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation are considered as ADR 
with the use of abemaciclib. The following information in Table 3 must be included in investigator-
sponsored protocols for hepatic monitoring: 
 
Hepatic Toxicity Dose Management Guidelines 
 
Monitor ALT prior to the start of abemaciclib therapy, every 2 weeks for the first 2 
months, monthly for the next 2 months, and as clinically indicated. 
 
CTCAE Grade for ALT and AST 
Action 
Grade 1 (>ULN-3.0 x ULN), Grade 2 (>3.0-5.0 x 
ULN), WITHOUT increase in total bilirubin above 
2 x ULN 
No dose modification required  
Persistent or Recurrent Grade 2, or Grade 3 
(>5.0-20.0 x ULN), WITHOUT increase in total 
bilirubin above 2 x ULN 
Suspend dose until toxicity resolves to baseline 
or Grade 1. Resume at next lower dose. 
Elevation in AST and/or ALT >3 x ULN WITH total 
bilirubin >2 x ULN, in the absence of cholestasis 
Discontinue abemaciclib 
Grade 4 (>20.0 x ULN) 
Discontinue abemaciclib 
 
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 in 
Appendix B. 
 
Diarrhea 
 
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: 


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• 
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.  
• 
Refer to table below for additional information for diarrhea management and dose modification. 
 
Diarrhea Dose Management Guidelines 
 
At the first sign of loose stools, start treatment with antidiarrheal agents, such as loperamide. 
 
CTCAE Grade  
Action 
Grade 1 
No dose modification required  
Grade 2 
If toxicity does not resolve within 24 hours to ≤ 
Grade 1, suspend dose until resolution. No dose 
reduction is required. 
Grade 2 that persists or recurs after resuming the 
same dose despite maximal supportive measures 
Suspend dose until toxicity resolves to ≤Grade 
1. 
Resume at next lower dose. 
Grade 3 or 4 or requires hospitalization 
 
Dose level reductions should be made in 50 mg increments. For example, if the starting dose of 
abemaciclib for a study is 150 mg q12 hours, dose reduction 1 would be 100 mg q12 hours, dose 
reduction 2 would be 50 mg q12 hours. 
 
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). 
 
Interstitial Lung Disease (ILD)/Pneumonitis  
 
ILD/Pneumonitis Dose Management Guidelines 
CTCAE Grade  
Action 
Grade 1-2 
No dose modification required  
Grade 2 that persists or recurs after resuming the 
same dose despite maximal supportive measures 
within 7 days to baseline or Grade 1 
Suspend dose until toxicity resolves to ≤Grade 
1. 
Resume at next lower dose. 
Grade 3-4 
Discontinue abemaciclib 
 
 
Non-hematological Toxicities (excluding Diarrhea, ALT Increased, and ILD Pneumonitis) 
 
Non-Hematological Toxicity Dose Management Guidelines (excluding Diarrhea, ALT 


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Increased, and ILD Pneumonitis) 
Event 
Action 
Grade 1-2 
No dose modification required  
Persistent or recurrent Grade 2 toxicity that does 
not resolve with maximal supportive measures 
within 7 days to baseline or Grade 1 
Suspend dose until toxicity resolves to baseline 
or ≤Grade 1. 
Resume at next lower dose. 
Grade 3-4 
 
Note: 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. 
 
4.2.2  
Dose Suspension and Cycle Delays 
 
Both dose suspension (within a cycle) and cycle delay are permitted. Study treatment 
may be held up to 14 days within a cycle or at start of next cycle to permit sufficient time 
for recovery from the toxicity. Patients not recovering from toxicity within 14 days should 
be considered for discontinuation at the discretion of the investigator. In exceptional 
circumstances, a delay >14 days is permitted upon agreement with the principal 
investigator (PI). 
 
A delay of a cycle due to holiday, weekend, bad weather, or other unforeseen 
circumstances will be permitted for a maximum of 7 days and not counted as a protocol 
deviation. In exceptional circumstances, a delay >7 days is permitted upon agreement 
with PI. 
4.3 
Fulvestrant Dose Modification and Management 
 
4.3.1  Guidelines for Use in Patients with Hepatic Impairment: 
 
A dose of 250mg is recommended for patients with moderate hepatic impairment (Child-
Pugh class B). Faslodex has not been evaluated in patients with severe hepatic 
impairment (Child Pugh class C). 
 
4.3.2   Guidelines for Use in Patients with Renal Impairment: 
 
Negligible amounts of Fulvestrant are eliminated in the urine. No adjustment is 
recommended. 
 
4.4 
Concomitant Medications/Treatments 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the patient is receiving at the time of enrollment 
or receives during the study must be recorded along with: 
 
Reason for use 
 
Dates of administration including start and end dates 
 


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All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care. 
 
All the concomitant medications and supportive therapy administered during the 30 days 
prior to the first dose until 30 days after the last dose must be recorded on the 
appropriate case report form (CRF). 
 
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.  
CYP3A Inducers 
Avoid concomitant use of CYP3A inducers and consider alternative agents. 
CYP3A Inhibitors 
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 
General Guidance for use of Radiotherapy in Combination with Abemaciclib 
 
Limited data are available with abemaciclib and radiotherapy or alternate dosing 
schedules (e.g. induction phase). Thus, caution should be exercised with administering 
abemaciclib with radiotherapy. 
 
4.4.1 
Palliative Medicine and Supportive Care 
 
In the event patients develop adverse events requiring palliative care, investigator will 
refer patient to primary care physician (PCP). 
 
4.3.2     Supportive Management for Diarrhea in Patients Receiving Abemaciclib 
 
Patients should receive instructions on the management of diarrhea.  In the event of 
diarrhea, supportive measures should be initiated as early as possible.  These include 
the following: 
 
At the first sign of loose stools, the patient should initiate anti-diarrheal 
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. 
 
If diarrhea does not resolve with anti-diarrheal therapy within 24 hours to at 
least Grade 1 (per CTCAE v 5.0), study abemaciclib treatment should be 
suspended until diarrhea is resolved to at least Grade 1. 
 
When abemaciclib treatment recommences, dosing should be adjusted as 
outlined in Section 4.2.1.  In severe cases of diarrhea, the measuring of 


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neutrophil counts and body temperature and proactive management of 
diarrhea with antidiarrheal agents should be considered. 
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia, broad-spectrum antibiotics such as fluoroquinolones should be 
considered. Patients with severe diarrhea or any diarrhea associated with severe nausea 
or vomiting should be carefully monitored and given intravenous fluid and electrolyte 
replacement as clinically indicated. 
 
4.5 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until: 
 
Maximum response (per investigator discretion based on clinical and/or 
imaging assessments) is obtained OR 
 
Disease progression as defined radiographic progression by RECIST v1.1 
criteria OR death OR symptomatic progression as clinically determined by 
the treating physician 
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Patient decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
4.6 
Duration of Follow Up 
Patients will be followed every 6 months after surgery for ctDNA blood collection. The 
follow up phase will continue until study completion at 5 years or until death, whichever 
occurs first.  
4.7 
Removal of Patients from Protocol Therapy 
Patients will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify UCI CFCCC via secure email (rparajul@hs.uci.edu and uci1879@hs.uci.edu), and 
document the reason for study removal and the date the patient was removed in OnCore. 
The patient should be followed-up per protocol.  
4.8 
Patient Replacement 
Patients will not be replaced   
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained as long as these assessments 
are completed within 28 days prior to registration. 
 
All screening procedures must be performed within 28 days prior to registration unless 
otherwise stated. The screening procedures include: 


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5.1.1 Informed Consent 
5.1.2 Screening Confirmation 
Patient information should be entered into Oncore within 1 business day of 
consent. Site is responsible for assigning subject ID. Subject IDs should follow a 
format with the unique site code followed by sequential patient ID. For example, 
Site Code-Sequential Number (i.e. for first patient the subject ID will be 01-01). 
Refer to Oncore SOP for Oncore data entry instructions.  
5.1.3 Medical history 
Complete medical and surgical history 
5.1.4 Demographics 
Age, gender, race, ethnicity 
5.1.5 Review subject eligibility criteria 
5.1.6 Review previous and concomitant medications 
5.1.7 Physical exam  
5.1.8 Vital signs, height and weight 
Temperature, pulse, respirations, blood pressure, weight and height (height only 
at screening) 
5.1.9 ECOG Performance status 
Refer to Appendix A 
5.1.10 Hematology 
Complete blood count (CBC) with differential  
5.1.11 Blood draw for correlative studies 
Blood collection for ctDNA. 
5.1.12 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT, AST, BUN, creatinine, electrolytes (sodium, potassium, 
calcium, chloride, bicarbonate), glucose, and total bilirubin. 
5.1.13 Tumor assessment 
To be performed with computed tomography (CT) of the chest (preferred with IV 
contrast) and abdomen/pelvis (preferred with IV and oral contrast) to rule out 
metastasis. CT abdomen/pelvis may be replaced with MRI Abdomen/pelvis 
(preferred with IV contrast) per clinical judgement of the treating physician. An 
MRI of the breast will also be required for RECIST 1.1 baseline assessment. 
Additional imaging is indicated at baseline if there is clinical suspicion for other 
organ involvement (i.e. MRI or CT brain and bone scan). Imaging is to be 
performed at baseline within 28 days of starting treatment 
 
 


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5.2 
Registration Procedures  
The below items must be reviewed and confirmation of eligibility must be completed by 
the PI and CRM prior to registration:  
 
Signed Informed consent  
 
Physical exam and complete medical and surgical history  
 
All screening labs 
 
Signed eligibility criteria  
 
 
Items must be reviewed by the PI and CRM at least 3 business days before planned 
treatment start date.  
5.3 
Procedures During Treatment 
5.3.1 
Prior to Each Treatment Cycle 
 Physical exam, vital signs 
 Hematology 
 Serum chemistries 
 Adverse events 
 Study drug accountability 
 Review previous and current concomitant medications 
 
Site must maintain an accurate and timely record of dispensing of study drug to 
subject, and receipt of all study drug and pill diaries. 
5.3.2 
Within 30 days after treatment termination 
 Physical exam, vital signs 
 Hematology 
 Serum chemistries 
 Adverse Events 
 Review previous and current concomitant medications 
 
5.2.3     Tumor Assessments 
 
MRI breast to be completed every 12 weeks (+/- 7 days) during treatment phase 
5.4 
Follow-up Procedures 
Patients will be followed every 6 (+/- 14 days)  months after surgery until patient comes 
off study due to study completion at 5 years, death, or withdrawal, whichever comes first 
 
Blood collection for ctDNA  
5.5 
Time and Events Table 
If baseline evaluations are conducted within 1 week prior to administration of protocol therapy, those 
assessments do not need to be repeated.  Scans must be done ≤4 weeks prior to the start of therapy.  
In the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. 
 
 
Baseline/Screening 
 
Treatment 
Phase 
 
Post-discontinuation 
 
-28 to -1 days 
Cycle 1 
Subsequent 
cycles 
End of 
Treatment 
Surgery 
Follow-
up 


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D1 
(-3d) 
D15 
(±3d) 
D1 
(-3d) 
Within 30 
days of 
last dose 
prior to 
surgery 
 
Every 6 
months 
(±14d)  
Assessment 
 
Informed 
Consent 
X 
 
 
 
 
 
 
History and PE 
X 
X 
 
X 
X 
 
 
Vital Signs 
X 
X 
X 
X 
X 
 
 
Baseline 
medical 
and 
oncology history 
X 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
 
X 
X 
 
 
ECOG 
Performance 
Status 
X 
X 
 
X 
X 
 
X 
Adverse Events 
 
X 
 
X 
X 
 
 
Tumor 
Measurements 
X 
 
 
 
 
 
 
CT CAP or CT 
chest/MRI 
Abd/Pelvis1 
X 
 
 
 
 
MRI Breast 
X 
X 
Every 12 weeks (±7d) after 
first dose until maximum 
response or progression, 
whichever occurs first 
 
 
 
CBC w/diff 
X 
X 
X 
X 
X 
 
 
CMP 
X 
X 
X 
X 
X 
 
 
Postmenopausal 
Confirmation 
X 
 
 
 
 
 
 
ctDNA 
(correlative 
study) 
X 
 
 
X2 
 
 
X 
Biopsy3 
 
 
 
 
X 
 
 
Tissue 
Submission 
X 
 
 
 
X 
X 
 
Administer 
Abemaciclib 
 
X 
X 
X 
 
 
 
Administer 
Fulvestrant 
 
X 
X 
X 
 
 
 
Study Drug 
Accountability 
 
 
 
X 
X 
 
 
1 CT Chest, abdomen and pelvis with contrast or CT chest/MRI Abdomen, Pelvis is required at screening to rule out 
metastasis 
2 Every 3 months during treatment 


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3 A fresh biopsy at time of progression is mandatory if clinically feasible. 
  
5.6 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Patient voluntarily withdraws from treatment (follow-up permitted);  
5.5.2 
Patient withdraws consent (termination of treatment and follow-up); 
5.5.3 
Patient is unable to comply with protocol requirements; 
5.5.4 
Patient demonstrates disease progression (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator); 
5.5.5 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 
Treating physician judges continuation on the study would not be in the patient’s 
best interest; 
5.5.7 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.8 
Lost to follow-up. If a research subject cannot be located to document survival 
after 3 attempts including 1 mailed certified letter, the subject may be considered 
“lost to follow-up.” All attempts to contact the subject during the two years must 
be documented and approved by the Data Monitoring Committee. 
6.0 
Measurement of Effect 
6.1 
Pathologic Complete Response (pCR) 
 No histologic evidence of microscopic invasive tumor at the primary tumor site in the 
surgical specimen (ypT0 or ypTis). 
6.2 
Antitumor Effect- Solid Tumors 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 
6.2.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
Evaluable for objective response. Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the definitions 
stated below. (Note: Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 


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Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable 
disease, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of 
the lesions.  
6.2.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm with 
spiral CT scan. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation therapy. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
spiral CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions 
 
Target lesions. All measurable lesions up to a maximum of 3 lesions per organ 
and 6 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be 
used as reference by which to characterize the objective tumor response. 
 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 6 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
6.2.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible 


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to the beginning of treatment and never more than 28 days before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Measurements should be performed on schedule even in the event of study 
treatment delay or omission. 
 
Imaging delays due to patient deterioration will not be considered a protocol 
deviation. 
 
Conventional CT and MRI. These techniques should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the 
chest, abdomen, and pelvis. MRI is also acceptable in certain situations (e.g. for 
body scans).  Scans will be done within 28 days prior to cycle 1 and after that 
every 8 weeks (+/- 7 days) until end of treatment. 
 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT 
in accurately measuring cancer lesions over time.  Note, however, that the PET 
portion of the CT introduces additional data which may bias an investigator if it is 
not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date and, 
because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next.  If 
new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI 
may be used instead of CT in selected instances. 
 
Cytology, Histology. These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
 


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6.2.4 
Response Criteria 
6.2.4.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the smallest sum LD recorded since 
the treatment started, or the appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
6.2.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions 
 
6.2.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
6.2.6 
Objective Response Rate 
ORR is defined as the percentage of patients who have achieved an objective 
confirmed overall complete response (CR) or partial response (PR) based on 
RECIST version 1.1 guidelines. 


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6.2.7 
Recurrence Disease Free Survival  
Recurrence disease free survival will be defined as the time from surgery until 
patient develops recurrence. 
 
6.3 
Safety/tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 5.0 for reporting of non-hematologic adverse 
events (http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for hematologic 
adverse events (Appendix #/letter). 
7.0 
ADVERSE EVENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
investigator will use CTCAE v 5.0 to assign AE severity grades. Investigators are responsible for 
monitoring the safety of patients who have entered this study and for alerting Eli Lilly 
Pharmaceuticals to any event that seems unusual, even if this event may be considered an 
unanticipated benefit to the patient. 
 
The investigator is responsible for the appropriate medical care of patients during the study. 
 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study. The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is otherwise explained. The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator. 
 
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect. 
 
After the ICF is signed, study site personnel will record via OnCore eCRF the occurrence and 
nature of each patient’s preexisting conditions, including clinically significant signs and symptoms 
of the disease under treatment in the study. In addition, site personnel will record any change in 
the condition(s) and any new conditions as AEs. Investigators should record their assessment of 
the potential relatedness of each AE to protocol procedure, investigational product, via OnCore 
eCRF. 
 
The investigator will interpret and document whether or not an AE has a reasonable possibility of 
being related to study treatment taking into account the disease, concomitant treatment or 
pathologies. 
 
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE. 
 
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study. 
 
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Eli Lilly Pharmaceuticals via Eli Lilly’s IIR Portal for Trial Management or via 
fax, clarifying if possible, the circumstances leading to any dosage modifications, or 
discontinuations of treatment. 


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7.1 
Definitions 
7.1.1 Event Definition 
  
Adverse event (AE) - An adverse event is any untoward medical experience or 
change of an existing condition that occurs during or after treatment, whether or 
not it is considered to be related to the protocol intervention.  
 
Unexpected Adverse Event [Modified from the definition of unexpected adverse 
drug experience in FDA regulations at 21 CFR 312.32 (a)] – An adverse event is 
unexpected if it is not listed in the investigator’s brochure and/or package insert; 
is not listed at the specificity or severity that has been observed; is not consistent 
with the risk information described in the protocol and/or consent; is not an 
expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse 
event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an 
unexpected event OR is an expected natural progression of any underlying 
disease, disorder, condition, or predisposed risk factor of the research participant 
experiencing the adverse event. 
 
Serious Adverse Event (SAE) [21 CFR 312.32] - Defined as any expected or 
unexpected adverse event that result in any of the following outcomes: 
 
Death 
 
Is life-threatening experiences (places the subject at immediate risk of 
death from the event as it occurred) 
 
Unplanned hospitalization equal or greater than 24 hours)) or 
prolongation of existing hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 
 
Any other adverse event that, based upon appropriate medical judgment, 
may jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the outcomes listed above (examples of 
such events include allergic bronchospasm requiring intensive treatment 
in the emergency room or at home, blood dyscrasias of convulsions that 
do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse). 
 
Unanticipated problem (UP) - Any incident, experience or outcome that meets 
all three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the 
following: a) the research procedures described in the protocol-related 
documents such as the IRB approved research protocol, informed 
consent document or Investigator Brochure (IB); and b) the 
characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcomes may have been caused by the drugs, devices 
or procedures involved in the research); AND 


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3. Suggests that the research places subjects or others at greater risk of 
harm (including physical, psychological, economic, or social harm) than 
previously known or recognized. 
 
Protocol Violation- A protocol violation is an accidental or unintentional change 
to or noncompliance with the IRB-approved protocol that increases risk or 
decreases benefit and/or affects the subject's rights, safety, welfare, and/or the 
integrity of the data. Examples of incidents that may be considered violations 
include: enrolling a participant who does not meet the inclusion criteria; obtaining 
verbal consent before the initiation of study procedures when the IRB requires 
signed, written informed consent; and failure to collect screening labs before 
initiation of study procedures [Reference: Policy #57 UCI HRPP Policy and 
Procedure Glossary].  
 
Protocol Deviation- A protocol deviation is an accidental or unintentional 
change to the research protocol that does not increase risk or decrease benefit 
or have a significant effect on the participant’s rights, safety or welfare, or on the 
integrity of the data. Deviations may result from the action of the participant, 
researcher, or staff. Examples: a rescheduled study visit, an omitted routine 
safety lab for a participant with previously normal values; or failure to collect an 
ancillary self-report questionnaire data (e.g., quality of life) [Reference: Policy 
#57 UCI HRPP Policy and Procedure Glossary]. 
Characteristics and Severity of Adverse Events 
 
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
CTCAE v5 is available at 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCA
E_v5_Quick_Reference_5x7.pdf 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 


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7.1.2 Characteristics and Severity of Adverse Events  
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
CTCAE v5 is available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCA
E_v5_Quick_Reference_5x7.pdf  
If no CTCAE grading is available, the severity of an AE is graded as follows:  
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.  
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.  
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
Fatal (grade 5): the event caused death. 
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. 
7.1.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
7.1.3.1 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
7.1.3.2 
Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe). 


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7.1.3.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
7.1.3.4 
Results in persistent or significant disability or incapacity. 
7.1.3.5 
Is a congenital anomaly/birth defect 
7.1.3.6 
Is an important medical event 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
7.2 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as per section 7.3.2: 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4:  Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
1. 
the current known adverse events listed in the Agent Information        
   Section of this protocol; 
2. 
the drug package insert; 
3. 
the current Investigator’s Brochure 


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7.3 
Reporting Requirements for Adverse Events 
Adverse events, serious adverse events, deviations, violations, and unanticipated problems must be entered into the clinical trial 
management system (CTMS), OnCore, and must also be reported to the following entities according to the timelines mentioned in 
the chart below. Serious adverse events collection will start at the time patient signs consent until 30 days after the end of 
treatment. Adverse events will be collected from the time the research patient begins treatment until 30 days after the end of 
treatment. All adverse events/serious adverse events should be followed until resolution or stabilization.  
 
Event Type  
Coordinating 
Center/Medical 
Monitor 
UCI IRB  
Eli Lilly Pharmaceuticals* 
CFCCC DSMB 
Unanticipated 
Problem (UP) 
Within 24 hours 
from date the site is 
aware of the event, 
the site should enter 
this information into 
OnCore. An email 
notification should 
also be sent via 
email to 
rparajul@hs.uci.edu 
and 
uci1879@hs.uci.edu.  
Within 5 
business days 
submit an 
Unanticipated 
Problem 
Report (UP). 
Current policy 
can be found 
here. 
Within 15 business days of learning of the 
event. Submit an SAE Form to Eli Lilly’s IIR 
Portal for Trial Management 
(https://www.lillyinvestigatorresearch.com)OR 
via fax (866-644-1697). Serious adverse events 
should be reported to Lilly using a CIOMS 
Form or other form acceptable to Lilly.  
Within 5 days from date PI is 
aware of the event. This 
information must be 
reported into OnCore.  
AEs and SAEs (non-
Unanticipated 
Problem)  
Please refer to 
section 7.4 for 
reporting 
timeframes on AEs 
and SAEs.     
N/A  
Only SAEs are required to be reported within 
15 business days of learning of the event. 
Please see section 7.6 below for additional 
reporting for SAEs that are non-UPs.   
Please refer to section 7.4 for 
clarification on reporting 
timeframes for AEs and SAEs.  
Non-compliance  
N/A 
N/A 
N/A 
Please refer to section 7.4 for 
reportable 
deviations/violations.   


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Serious or 
continuing non-
compliance  
Within 24 hours via 
email to 
rparajul@hs.uci.edu 
and 
uci1879@hs.uci.edu    
Within 5 
business days 
submit a New 
Information 
Report 
N/A 
Within 5 days from date PI is 
aware of the event.  
Prospective/Planned 
Deviations  
At least 5 business 
days prior to the 
event via email to 
rparajul@hs.uci.edu 
and 
uci1879@hs.uci.edu 
for approval.    
At least 48 
hours prior to 
date the 
request is 
needed by. 
Submit a  
Prospective 
Deviation 
Request form 
N/A  
At the time of progress 
review as aggregate reports.  
*Patients who become pregnant must be reported along same timelines as SAE.  Please reference section 7.5 below in regards to additional 
safety information required to be reported to Eli Lilly Pharmaceuticals for subjects who become pregnant. 
 
7.4 
Additional Reporting Requirements to CFCCC DSMB  
Site must report AE, SAE, deviations, violations, and unanticipated problems according to their institutional policies. 
Institutions must also report AE, SAE, deviations, violations, and unanticipated problems to the DMSB in the following timeframes: 
 
Adverse Events/Serious Adverse Events 
Event Type  
Reporting Timeframe to 
CFCCC DMSB  
(Notification is done by 
entering this information into 
OnCore within the timelines 
below) 
Serious Adverse Events (all attributions) that meet all of the following 
criteria: 
 
Unexpected 
 
Grades 3-5 
5 business days from date the 
PI is aware of the event 


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 
Occurring during treatment or within 30 days of the end 
of treatment* 
Adverse Events that meet all of the following criteria: 
 
Unexpected 
 
Study related (possibly, probably, or definitely) 
 
Grades 3-4 
 
Occurring during treatment or within 30 days of the end 
of treatment* 
5 business days from date the 
PI is aware of the event 
All other Adverse Events and Serious Adverse Events should be reported 
as noted in the ‘Recording of Events’ section 
Prior to each scheduled 
progress review.  
* Investigators are not obligated to actively seek information regarding the occurrence of new AEs or SAEs beginning after the 30-
day post-treatment period. However, if the investigator learns of such an event and that event is deemed relevant to the study, 
he/she should promptly document and report the event. 
 
Deviations and Violations 
Event Type  
Reporting Timeframe to 
CFCCC DSMB 
(Notification is done by 
entering this information 
into OnCore within the 
timelines below) 
Violations as defined above (e.g. wrong dosage of drug 
administered, safety procedures not being conducted at 
specific time points). 
5 business days from the date 
the PI is aware of the event 
Deviations as defined above, including: 
 Planned deviations (e.g. rescheduling a visit that will be 
out of window due to a holiday) 
 Unplanned deviations (e.g. rescheduled visit, a missed 
routine safety laboratory test for a participant with 
previously normal values) 
Prior to each scheduled 
progress review  
 
 
 
 


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7.5 
Additional Clinical Reporting Requirements to Eli Lilly Pharmaceuticals 
Eli Lilly Pharmaceuticals requires that all SAEs related to study drug are reported via Eli Lilly’s IIR 
Portal for Trial Management (https://www.lillyinvestigatorresearch.com) OR via fax (866-644-
1697). Serious adverse events should be reported to Lilly using a CIOMS Form or other form 
acceptable to Lilly. Eli Lilly Pharmaceuticals does not require the report of other events of special 
interest.   
 
7.6 Other Non-Clinical Reporting Guidelines to Eli Lilly Pharmaceuticals 
Other information such as milestone dates, milestone dates met, enrollment updates, protocol 
amendments, site information, and expenses (invoices) can be updated in Eli Lilly’s IIR Portal for 
Trial Management (https://www.lillyinvestigatorresearch.com) by the study members assigned by 
the principal investigator. 
8.0 
DRUG INFORMATION 
8.1 
Abemaciclib 
 
A list of the adverse events and potential risks associated with Abemaciclib can be found in the 
investigator brochure available in OnCore 
 
 
Other names for the drug(s): Verzenio 
 
 
Classification - type of agent: Antineoplastic 
 
 
Mode of action: Cyclin-dependent kinase inhibitor 
 
 
Storage and stability: Store at room temperature, refer to product label for specific 
storage range and instructions.” 
 
 
Protocol dose: 150 mg BID, Abemaciclib will be provided in 50mg tablets only 
 
 
Preparation: N/A 
 
 
Route of administration for this study: Oral 
 
 
Availability: Provided by Eli Lilly 
 
 
Side effects: Common side effects are Diarrhea, Neutropenia, Nausea, abdominal 
pain, fatigue, anemia, leucopenia, vomiting, thrombocytopenia, thromboembolism 
 
 
 
8.2 
Fulvestrant 
 
A list of the adverse events and potential risks associated with Fulvestrant are found in package 
insert. 
 
 
Other names for the drug(s): Faslodex 


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 
Classification - type of agent: Antineoplastic 
 
 
Mode of action: Estrogen receptor antagonist 
 
 
Storage and stability: Refrigerate, 2 to -8°C, protect from light, store in original 
cartoon until time of use 
 
 
Protocol dose: Supplied at 50mg/ml. Protocol dose 500 mg. 
 
 
Preparation: Solution 
 
 
Route of administration for this study: Intramuscular 
 
 
Availability: Commercially available 
 
 
Incompatibility: There are no known drug-drug interactions. Fulvestrant does not 
significantly inhibit any of the major CYP isoenzymes, and studies of co- 
administration of fulvestrant with midazolam indicate that therapeutic doses of 
fulvestrant have no inhibitory effects on CYP3A4 or alter blood levels of drug 
metabolized by that enzyme. Also, although fulvestrant is partly metabolized by 
CYP3A4, a clinical study with rifampin, an inducer of CYP3A4, showed no effect on 
the pharmacokinetics of fulvestrant. Clinical studies of the effect of strong CYP3A4 
inhibitors on the pharmacokinetics of fulvestrant have not been performed. 
 
 
Handling: Use appropriate precautions for receiving, handling, administration, and 
disposal. Gloves (single) should be worn during receiving, unpacking, and placing in 
storage. NIOSH recommends double gloving, a protective gown, ventilated 
engineering controls (a class II biological safety cabinet or a compounding aseptic 
containment isolator), and closed system transfer devices (CSTDs) for preparation. 
Double gloving and a protective gown are recommended during administration 
(NIOSH 2016). 
 
 
Side effects: Fatigue, Headache, Hot flash, Anemia, Nausea, cough, increase in 
creatinine, peripheral edema, dizziness, pruritus, skin rash, back pain, anorexia, 
hypersensitivity reactions, and thromboembolism. Increase hepatic enzymes also can 
occur. 
 
Hot flashes (23.5%) are the most commonly reported adverse reaction to fulvestrant 
during second line hormonal therapy for breast cancer. Vaginal irritation (3.4%) has 
also been reported with fulvestrant. 
 
UTI adverse reactions occurred in up to 9.3% of patients receiving 
fulvestrant.  
 
Joint disorders have been reported in 9.3% of patients. 
 
Others include nausea, vomiting, constipation, diarrhea and abdominal pain, 
headache, back pain, and pharyngitis. 
 


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Thromboembolism has been reported in patients treated with fulvestrant (3.5%). The 
incidence of thrombosis is less than that reported with tamoxifen (6.5%) or megestrol 
(4.7%) during clinical trials. 
 
Injection site reactions with mild transient pain and inflammation occurred in 7% of 
patients (1% of treatments) given the single 5ml injection of fulvestrant and 
withdrawal secondary to that was 2.5%. 
 
Other adverse events reported as drug-related and seen infrequently (< 1%) include 
thromboembolic phenomena, myalgia, vertigo, and leukopenia. 
 
Vaginal bleeding has been reported infrequently (< 1%), mainly in patients during the 
first 6 weeks after changing from existing hormonal therapy to treatment with 
fulvestrant. If bleeding persists, further evaluation should be considered. 
 
 
Contraindications: Hypersensitivity reaction 
 
 
Warning and precaution:  
-Blood disorders: Should be used with caution in patients with bleeding diathesis, 
thrombocytopenia or anticoagulant use 
-Hepatic Impairment: A 250mg dose is recommended in patients with moderate 
hepatic impairment 
-Pregnancy: Women should be advised of potential hazard to the fetus and to avoid 
becoming pregnant while receiving Faslodex 
 
8.3 
Agent Accountability 
Accountability for the study drug at the study center is the responsibility of the Investigator. The 
Investigator will ensure that the study drug is used only in accordance with this protocol. Where 
allowed, the Investigator may choose to assign drug accountability responsibilities to a 
pharmacist or other appropriate individual. 
 
The Investigator or delegate will maintain accurate drug accountability records indicating the 
drug’s delivery date to the site, inventory at the study center, use by each patient, and 
destruction. 
 
These records will adequately document that the patients were provided the doses as specified in 
the protocol and should reconcile all study drug received from Eli Lilly Pharmaceuticals. 
 
Study drug must not be used for any purpose other than the present study. Study drug that has 
been dispensed to a patient and returned unused must not be redispensed to a different patient. 
 
Patients will receive instructions for home administration of Abemaciclib according to the regimen 
description above. Abemaciclib is to be taken twice a day. If doses of Abemaciclib are missed or 
held, the patient should not make up for the missed doses. Patients will be given a study 
medication diary to complete at home for Abemaciclib. Compliance with the dosing regimen will 
be assessed based on completion of the drug diary and return of unused drug (or empty bottles). 
 
IMP Destruction 
IMP will be destroyed by the sites according to their institutional policies. Documentation of IMP 
destruction should be made available to Eli Lilly Pharmaceuticals at the end of the study. 
 
IMP Returns 


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Eli Lilly Pharmaceuticals will not accept returned IMP 
 
9.0 
CORRELATIVE STUDY 
Molecular analysis in the form of Next Generation Sequencing (NGS) will be performed on the 
treatment naïve archival breast tissue, on the breast tissue at the time of recurrence and on the 
surgical specimen. Blood will be collected as well for analysis of ctDNA before enrollment, every 
3 months while on the treatment and then every 6 months (after definitive surgery) until the end 
of the study at five years. The molecular analysis by NGS will be done by Tempus using their 
standard platform. 
 
Correlative Study Objective: 
1. 
To determine if genomic analysis of patient matched breast tissue samples and serial 
mutational tracking of ctDNA can identify new mechanisms of endocrine resistance and the 
way Abemaciclib overcomes endocrine resistance 
2. 
To determine the mechanism of response or resistance to Abemaciclib 
3. 
To determine biomarkers related to the Rb pathway 
 
Collection of tumor samples (archival, at time of recurrence, and from surgery) and ctDNA blood 
are mandatory. 
 
 
 
10.0 
STATISTICAL CONSIDERATIONS 
Pathological response (pCR) is a tool to measure the efficacy of Neo-Adjuvant therapy. A 
complete pCR is defined as the absence of invasive cancer in the tumor and/or the axillary 
lymph node in the surgical pathology specimen after undergoing Neo-Adjuvant therapy. 
Chemotherapy can shrink HR- positive tumors and facilitate better surgical options, but is less 
likely to achieve a pathologic complete response (pCR) in HR-positive cancers, especially 
luminal A cancers, than for more proliferative histologies. Multiple metaanalysis have shown 
that pCR has prognostic implications even in patients with HR+ breast cancer. However, a 
limitation of using pCR to predict outcomes in patients with ER+ disease is that only 2 to 10 
percent of patients with ER + disease achieve a pCR with NACT. In the post-menopausal 
setting, Aromatase Inhibitors are recommended over Tamoxifen as Neoadjuvant endocrine 
therapy based on clinical trials and meta-analysis. AIs resulted in higher clinical response rate 
(OR 1.69, 95% CI 1.36-2.10), radiologic response rate (OR 1.49, 95% CI 1.18-1.89), and BCS 
rate (OR 1.62, 95% CI 1.24-2.12) compared with tamoxifen (18). 
 
Several trials have also investigated the role of endocrine therapy in combination with other 
targeted therapies. For example, in the randomized phase II UNICANCER-NEOPAL study, the 
combination of neoadjuvant palbociclib and letrozole resulted in slightly lower pCR rates 
compared with neoadjuvant third-generation chemotherapy, but the rates of clinical response 
and breast-conserving surgery were similar, with less frequent serious adverse events (19). 
Another study compared different doses of neoadjuvant fulvestrant (500 mg/month versus 250 
mg/month) given for 16 weeks prior to surgery (20). Similar to what has been observed in the 
metastatic setting, the study demonstrated that the higher dose of fulvestrant was superior 
and had a greater antiproliferative effect. At week 16, tumor response rates were 22.9 and 
20.6% for fulvestrant 500 and 250 mg, respectively, with considerable decline in all markers by 
both imaging and the ER/PR scoring method. 
 


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Several ongoing trials are investigating the role of combination therapy, including the 
combination of AIs with cyclin-dependent kinase (CDK) 4/6 inhibitors (NeoMONARCH), PI3K 
inhibitors (LORELEI), and dual endocrine therapy (ALTERNATE). 
 
The NeoMONARCH study randomly assigned postmenopausal women with early stage HR+ 
breast cancer to Neoadjuvant therapy with Anastrozole, Abemaciclib or Anastrozole with 
Abemacilib. The study met its primary endpoint by showing that Ki67 levels were significantly 
reduced in breast cancer cells from the 107 patients who received abemaciclib, either alone or 
in combination with anastrozole, compared with the 54 patients who received anastrozole only. 
Treatment with abemaciclib plus anastrozole led to a reduction in tumor size in most 
patients, as assessed by clinical and radiologic evaluation. Patients in this study received 
Abemaciclib only for two weeks. Therefore, extending Neo- Adjuvant Abemaciclib (beyond two 
weeks) as proposed in the current trial and combining it with high dose Fulvestrant is expected 
to achieve a higher response rate, greater anti-proliferative effect as measured by the Ki-67 
index and perhaps improve Breast conservation surgery (21). 
Similarly, the MONARCH 2 study compared the efficacy and safety of abemaciclib plus 
fulvestrant with fulvestrant alone in patients with advanced HR + breast cancer. Abemaciclib plus 
fulvestrant significantly extended PFS versus fulvestrant alone (median, 16.4 v 9.3 months; 
hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P < .001). In patients with measurable disease, 
abemaciclib plus fulvestrant achieved an ORR of 48.1% (95% CI, 42.6% to 53.6%) compared 
with 21.3% (95% CI, 15.1% to 
27.6 
%) in the control arm (22). 
 
The MONALEESA-3 study was a phase III study evaluated ribociclib plus fulvestrant in patients 
with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced 
breast cancer who were treatment naïve or had received up to one line of prior endocrine therapy 
in the advanced setting. Among patients with measurable disease, the overall response rate was 
40.9% for the ribociclib plus fulvestrant arm and 28.7% for placebo plus fulvestrant (23). 
The cohort in the proposed trial have had local recurrence while on adjuvant endocrine therapy. 
Hence, they are expected to have molecular evidence of endocrine resistance. Since Fulvestrant 
and CDK 4/6 inhibition have been shown to benefit patient with endocrine resistance, we expect 
that Neo-Adjuvant Abemaciclib with Fulvestrant with achieve a response rate, greater 
antiproliferative effect as measured by the Ki-67 index and perhaps improve Breast conservation 
surgery too. 
10.1 
Study Design 
This study is a prospective, open-label, single-centered, phase II trial.  
 
10.2 
Sample Size and Accrual and Data Analyses Plans 
Tumor Registry data at UCIMC shows that we have had 960 patients with Hormone 
Receptor positive breast cancer from 2012-2017. The 2018 data is currently not 
populated by the tumor registry. Similarly, from 1/1/14 to 6/14/2019, there have been 456 
patients accrued in breast cancer trials out of which, 155 patients were enrolled in 
treatment trials. In order to obtain 30 evaluable breast cancer participants to examine the 
primary hypothesis, we will need to screen 680 invasive breast cancer patients (this is 
clearly possible due to the cohort of 960 patients from 2012-2017). Based on the data 
from California Cancer Registry and estimated percentage of recurrence, we estimate 
that approximately around 10% of 680 invasive breast cancer patients are post-
menopausal, have histologically been confirmed with HR+, have localized non-metastatic 
breast cancer and will have recurrence. Of the 68 patients, we estimate that there are 59 
(87% of 68) patients who are also on adjuvant endocrine therapy. The mutation ESR1 is 


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detected in 11-54% of patients with advanced breast cancer especially during the 
progression of hormonal therapy. Therefore, we estimate that there are 32 (54% of 59) 
patients who have ESR1 gene mutation/any known molecular evidence of endocrine 
resistance. To take into account of 5% attribution, we will need to enroll 32 subjects to 
receive the study treatment to ensure that there are 30 evaluable breast cancer 
participants. The plan of enrollment is over a four-year period. Hence, with the adequate 
number of patients justified from UCIMC tumor registry data and extending the period of 
enrollment from to four years, enrolling the sample size of 30 patients over a period of 
four years is feasible. 
 
Table x1:Power and sample sizes of Simon's two-stage design  
N 
n1 
r1 
r2 
Type 1 
Error 
Power 
EN0 
Probability 
of early 
stopping 
p0 
p1 
29 
10 
1 
5 
0.0471 
0.8051 
15 
0.7361 
0.1 0.3 
 
Table X1 presents sample size of Simon’s two-stage design. Where n is the total number 
of subjects, n1 is the number of subjects accrued during stage 1, if r1 or fewer responses 
are observed during stage 1, the trial is stopped early for futility. If r2 or fewer responses 
are observed by the end of stage two, then no further investigation of the drug is 
warranted, EN0 is the expected sample size for the trial when response rate is p0 and p0 
and p1 are the response probabilities under the null and under the alternative hypothesis. 
Thus, the null hypothesis that the true response rate is 10% will be tested against a one-
sided alternative. In the first stage, 10 patients will be accrued. If there are one or fewer 
responses in these 10 patients, the study will be stopped. Otherwise, 19 additional 
patients will be accrued for 29. The null hypothesis will be rejected if 6 or more responses 
are observed in 29 patients. This design will yield a type I error rate of 0.0471 and power 
of 80% when the true response rate is 0.3. Thus, we anticipate recruiting 29 evaluable 
participants with at least 10 in stage 1. (Simon 1984, Jung et al 2004) (16, 17).Given the 
sample size of 30 participants, power in the statistical design will be low for the 
secondary  and exploratory endpoints. Efficacy of the study as measured by estimating 
the objective response rate in the breast and/or the axillary lymph nodes or determining if 
the combination of Abemaciclib and Fulvestrant increases the percentage of patients who 
undergo breast conserving surgery will be measured by constructing 95% CI. We plan to 
use survival analysis methods such as Kaplan- Meier estimates of survival probability for 
univariate analysis and log rank tests in order to test for differences among different 
patient characteristics such age group for recurrence or disease-free survival. For 
multivariate analysis in order to examine survival adjusted for a number  of covariates we 
plan to use the Cox proportional hazards model.In order to examine the safety and 
toxicity which will be determined by the incidence of treatment-emergent, treatment-
related adverse events (TRAEs), and serious adverse events (SAE) we plan to monitor 
side effects and adherence to the protocol throughout the duration of the study. Interim 
analyses will be performed to assess the presence of side effects. Contingency tables will 
be constructed to compare the proportion of patients with side effects by study 
characteristics as age, race ethnicity and other clinical and epidemiologic characteristics. 
Distributions of all data items will be generated and examined for the presence of outliers, 
in order to assess the general form of the distributions, and to compute measures of 
central tendency and variability. Trellis graphics will be used for data display including 
histograms, boxplots, and Q-Q normal plots. In addition, we plan to examine if genomic 
analysis of patient matched breast tissue samples and serial mutational tracking of 
circulating tumor DNA can identify new mechanisms of endocrine resistance and how 


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Abemaciclib overcomes endocrine resistance. For the analyses with matched pair tissue 
data we will use paired t tests or Wilcoxon sign rank statistical analysis in order to test 
differences in recurrent and treated breast tissue. We plan to measure absolute values 
and changes in circulating tumor DNA and correlate them with endocrine resistance. If 
serial monitoring of ctDNA can provide markers of resistance, we will quantify endocrine 
resistance as a composite outcome that will be quantified as dichotomous variable if it 
happens (yes or no) and at what time interval during our study. We will start our analysis 
by using frequency table analysis in order to examine the relationship between resistance 
or sensitivity and specific mutations. 
 
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by their own institution’s COI committee. All investigators will follow 
the University conflict of interest policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
11.2 
Data Completion 
11.2.1   OnCore Data Entry 
 
Data, as indicated by Sponsor, will be entered into OnCore – UC Irvine’s Clinical Trial 
Management system. The Investigator is responsible for ensuring all entries are accurate 
and correct. The Investigator must maintain accurate source data that support OnCore 
data entry. All data will be entered as per Sponsor’s specification and timeframe. 
 
11.2.2   Recording of Events 
 


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All investigator initiated treatment trials require that adverse events, serious adverse 
events, deviations, and unanticipated problems be entered into the clinical trial 
management system (CTMS), OnCore. All entries must be entered in OnCore within the 
timelines specified in section 7.4-7.6 of being aware of the adverse event, serious 
adverse event, violation, deviation, or unanticipated problem. Adverse events and 
violations/deviations and adverse events that are unanticipated problems that require 
prompt reporting to the DSMB must be entered into OnCore according to the timelines as 
specified in section 7.3-7.5 
 
11.3 
Data and Safety Monitoring/Auditing 
11.3.1 Quality Assurance  
Quality assurance activities will be conducted as per UC Irvine Chao Family 
Comprehensive Cancer Center’s Quality Assurance Monitoring and Auditing Plan and at 
the discretion of the CFCCC Data and Safety Monitoring Board in order to ensure patient 
safety and data integrity oversight. By conducting internal monitoring and auditing, the 
CFCCC will ensure compliance with high quality standards and all applicable regulations, 
guidelines, and institutional policies. Trial monitoring and auditing may be completed 
remotely or on-site by the Quality Assurance Officer. Participating sites may follow their 
own internal quality assurance policies in order to maintain patient safety and data 
integrity oversight. The investigator must permit study-related monitoring/auditing and 
provide access to study-related materials.  
 
11.3.2 Data and Safety Monitoring Plan 
This is a risk level 2 study, as defined in the Chao Family Comprehensive Cancer 
Center (CFCCC) Data and Safety Monitoring Plan (DSMP) because it is a study in which 
the IND is exempt by the FDA. 
 
The Principal Investigator (PI), co-investigator, clinical research coordinator, and 
statistician are responsible for monitoring of data and safety for this study. For studies 
that have stopping rules for safety and efficacy, the PI will be responsible for the 
implementation and make changes as applicable. The CFCCC Data and Safety 
Monitoring Board (DSMB) is an independent body responsible for the safety of study 
subjects as well as the data integrity of the protocol. Data and safety will be reported to 
the DSMB with submission of progress reports that include aggregated reports of 
adverse events, serious adverse events, deviations, and violations. In addition, all 
adverse events, deviations, and violations will be reported promptly to the DSMB for 
review according to section 7.4 and section 7.5. 
11.4 
Protocol Deviation 
All protocol deviations will be reported in accordance with UCI IRB, UCI CFCCC Stern 
Center policies and the participating site’s IRB policies. 
11.5 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
 


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The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.6 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
11.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
12.0 
REFERENCES 
 
1. Gralow JR, Burstein HJ, Wood W, et al. Preoperative therapy in invasive breast cancer: 
pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol 2008; 
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2. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical 
benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 384:164. 
 
 
3. Von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete 
response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer 
subtypes. J Clin Oncol 2012; 30:1796. 
 
4. Hayes DF. Targeting adjuvant chemotherapy: a good idea that needs to be proven! J Clan 


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Page 47 of 57 
 
Oncol 2012; 30:1264. 
 
5. Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with 
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9. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical 
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10. Ellis MJ, Coop a, Singh B, et al. Letrozole is more effective neoadjuvant endocrine therapy 
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11. Alba E, Calvo L, Albanell J, et al. Chemotherapy (CT) and hormonotherapy (HT) as 
neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006-03, 
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12. Spring LM, Gupta A, Reynolds KL, et al. Neoadjuvant Endocrine Therapy for Estrogen 
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13. Semiglazov VF, Semiglazov VV, Dashyan GA, et al. Phase 2 randomized trial of primary 
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14. Palmieri C, Cleator S, Kilburn LS, et al. NEOCENT: a randomized feasibility and 
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15. Alba E, Calvo L, Albanell J, et al. Chemotherapy (CT) versus hormone therapy (HT) as 
neoadjuvant treatment in luminal breast cancer: a multicenter, randomized phase II study 
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16. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar; 
10(1):1-10. PubMed PMID: 2702835 
 
17. Jung SH, Lee TY, Kim KM, George S (2004). Admissible two-stage designs for phase II 
cancer clinical trials, Statistics in Medicine 23: 561-569. 
 
18. Spring LM, Gupta A, Reynolds KL, et al. Neoadjuvant Endocrine Therapy for Estrogen 
Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis. JAMA Oncol 
2016; 2:1477. 
 
19. Cottu P, D'Hondt V, Dureau S, et al. LBA9-Letrozole and palbociclib versus 3rd generation 
chemotherapy as neoadjuvant treatment of breast cancer. Results of the UNICANCER-


Protocol #: UCI 18-79 
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CONFIDENTIAL 
This material is the property of the UC Irvine Chao Family Comprehensive Cancer Center. Do not disclose or use except as authorized in writing 
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eoPAL study. ESMO 2017. 
 
20. Kuter I, Gee JM, Hegg R, et al. Dose-dependent change in biomarkers during neoadjuvant 
endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study. 
Breast Cancer Res Treat 2012; 133:237. 
 
21. Hurvitz et all. Cancer Discovery. 2017 Feb; 7(2):119-120. 
 
22. Sledge GW, Toi M, Bourayou N, Llombart-Cussac C. J Clin Oncol. 2017 Sep 1; 
35(25):2875- 2884. 
 
23. Slamon DJ, Neven P, Taran T, Jerusalem G. Phase III Randomized Study of Ribociclib and 
Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-
Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20; 
36(24):2465-2472 
 
 
13.0 
APPENDICES 
 
APPENDIX A: ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
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. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 


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5 
Dead. 
0 
Dead. 
 
 
APPENDIX B: Liver Safety: Suggested Actions and Follow-up Assessments 
 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and 
may be required in follow-up with patients in consultation with the principal investigator. 
 
Hepatic Monitoring Tests  
Hepatic Hematology 
 
 
 
 
 
Haptoglobin 
Hemoglobin (HGB) 
Hematocrit (HCT) 
 
 
 
 
 
Hepatic Coagulation 
Erythrocytes (RBC) 
 
 
 
 
 
Prothrombin Time (PT) 
Leukocytes (WBC) 
 
 
 
 
 
Prothrombin Time, INR 
Neutrophils 
Lymphocytes 
 
 
 
 
 
 
Hepatic Serologies 
Monocytes 
 
 
 
 
 
 
Hepatitis A antibody, total 
Eosinophils 
 
 
 
 
 
 
Hepatitis A antibody, IgM 
Basophils 
 
 
 
 
 
 
Hepatitis B surface antigen 
Platelets (PLT)  
 
 
 
 
 
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 
Alanine aminotransferase (ALT)  
 
 
 
Recommended Autoimmune Serology 
Aspartate aminotransferase (AST) 
 
 
 
Anti-nuclear antibody 
Gamma-glutamyl transferase (GGT) 
 
 
 
Anti-smooth muscle antibody 
Creatine phosphokinase (CPK)  
 
 
 
Anti-actin antibody 
 
 
 
APPENDIX C: Inducers and Strong Inhibitors of CYP3A 
 
The information in this appendix is provided for guidance to investigators and does not preclude 
the use of these medications if clinically indeicated  
 
Strong Inducers of CYP3A 
Carbamazepine                                                          Rifapentine 
Dexamethasone                                                         Rifabutin 
Phenobarbital/phenobarbitone                                   Rifampin 
Phenytoin                                                                St. John’s Wort  
Moderate Inducers of CYP3A 
Bosentan                                                                 Primidone 
Lenisurad                                                                Telostristat ethyl 
Modafinil 
Strong Inhibitors of CYP3A 
Aprepitant                                                                Itraconazole 


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Ciprofloxacin                                                           Ketoconazole 
Clarithromycin                                                         Nefazodone 
Conivaptan                                                              Posaconazole 
Diltiazem                                                                 Troleandomycin 
Erythromycin                                                           Verapamil 
Fluconazole 
 
APPENDIX D: Pill Diaries 
 
Pill Diary Cycle 1 
 
Day 1 (Same day as 500mg Fulvestrant Injection) 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of morning dose: __________ 
Comments:  
Day 2 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 3 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 4 
Date: _______________ 
UCI 18-79 Abemaciclib Pill Diary                                                                       Cycle: 1 
Subject Initials: ___ ___ ____     Subject ID: __________________    Current Total Dosage: ____________ 
Dosing Instructions: 
Abemaciclib will be taken twice a day, once in the morning and once in the evening. 
If you forget to take a dose, do not make up the dose and record that the dose was skipped. 
Please record the date and times you take the Abemaciclib. 
Please remember to bring your bottles and Pill Diary to each clinic visit. 
If you experience any symptoms, please do not take the dose and contact the Study Team. 
 
Treating Investigator: ___________________ 
Nurse Navigator: _______________________                                    Next Clinic Visit: _________________ 
Study Coordinator: _____________________ 
 


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Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 5 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 6 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 7  
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 8 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 9 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 10 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 11 
Date: _______________ 


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Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 12 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 13 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 14 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 15 (same day as 500mg Fulvestrant injection) 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 16 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 17 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 18 
Date: _______________ 


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Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 19 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 20 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 21 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 22 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
 
 
 
 
 
Pill Diary Cycle 2 and Forward 
 


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Day 1 (Same day as 500mg Fulvestrant Injection) 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of morning dose: __________ 
Comments:  
Day 2 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 3 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 4 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 5 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
UCI 18-79 Abemaciclib Pill Diary                                                       Cycle: ________       
Subject Initials: ___ ___ ____    Subject ID: _____________         Current Total Dosage: ______________ 
Dosing Instructions:  
Abemaciclib will be taken twice a day, once in the morning and once in the evening. 
If you forget to take a dose, do not make up the dose and record that the dose was skipped. 
Please record the date and times you take the Abemaciclib. 
Please remember to bring your bottles and Pill Diary to each clinic visit. 
If you experience any symptoms, please do not take the dose and contact the Study Team. 
 
Treating Investigator: _____________________ 
Nurse Navigator: ________________________                            Next Clinic Visit: _________________ 
Study Coordinator: _______________________ 
 


Protocol #: UCI 18-79 
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by the study sponsor. 
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Comments:  
Day 6 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 7  
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 8 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 9 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 10 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 11 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 12 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  


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by the study sponsor. 
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Day 13 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 14 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
Day 15  
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 16 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 17 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 18 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 19 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 20 
Date: _______________ 


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Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 21 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
Day 22 
Date: _______________ 
Dose taken in the morning: 
Dose taken in the evening: 
__________ mg 
__________mg 
Time of morning dose: __________ 
Time of evening dose: __________ 
Comments:  
 
APPENDIX E: Definitions 
 
Inflammatory Disease: Erythema AND peau d’orange involving 1/3 or more of the breast with a 
histological diagnosis of breast cancer. The finding of focal dermal lymphatic involvement on histology 
does not constitute inflammatory breast cancer. 
 
PEPI Score: The PEPI Score (preoperative endocrine prognostic index) is a score that is used in 
clinical trials to assess response to Neo-Adjuvant endocrine therapy. The PEPI score takes into 
account the tumor and nodal stage, level of ER expression and Ki 67 following neoadjuvant endocrine 
therapy. 


UCI IRB: Biomed Consent – May 2019 
 
 
UNIVERSITY OF CALIFORNIA, IRVINE 
CONSENT TO ACT AS A HUMAN RESEARCH SUBJECT 
 
UCI 18-79:  A Phase II Open Label Trial of Neo-Adjuvant Abemaciclib with Fulvestrant in Patients 
Who Develop Localized Recurrence While on Adjuvant Endocrine Therapy with Molecular 
Evidence of Endocrine Resistance 
(MP 09/09/20, Main ICF v4 09/09/2020) 
 
Lead Researcher 
Ritesh Parajuli, HS Assistant Clinical Professor  
Department of Medicine  
(714) 456-5153; rparajul@uci.edu 
24-Hour Telephone Number/Pager: (714) 506-2420 
 
Other Researchers  
Rita Mehta, MD 
Kari Kansal, MD 
Karen Lane, MD 
Erin Lin, MD 
Paul Coluzzi, MD 
Andreea Nanci, MD 
Rupali Nabar, MD 
Khosrow Mahdavi, MD 
 
STUDY LOCATION(S):  
UC Irvine Health 
Chao Family Comprehensive Cancer Center  
101 The City Drive South, Building 23  
Orange, CA 92868 
 
UC Irvine Health – Newport Cancer Center  
1640 Newport Blvd 
Costa Mesa, CA 92627 
 
STUDY SPONSOR(S):  
UCI 
 
 
 
SUMMARY OF KEY INFORMATION: 
 
The information provided in this box includes a brief yet complete summary of key information 
about the research, presented first as required by the federal regulations. Some sections that 
require additional information may be repeated later in this document. 
 
Participation is Voluntary 
You are being asked to participate in a research study.  Participation is completely voluntary.  Please 
read the information below and ask questions about anything that you do not understand.  A 
researcher listed above will be available to answer your questions. 
 
Study Purpose 
The purpose of this research study is to determine if the combination of abemaciclib plus fulvestrant 
before surgery will destroy as much cancer as possible that will allow a complete pathologic response 
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to be achieved. A Complete pathologic response is defined as the absence of breast cancer in the 
breast and/or the axillary (a person's armpit) lymph nodes in the surgical specimen.  
 
You should also have demonstrated evidence of resistance to endocrine therapy by next generation 
sequencing of the breast tissue. Next generation sequencing is a test that looks for mutations in your 
genes.  
 
Study Procedures 
This study will consist of a screening period of up to 28 days. After screening procedures have been 
completed, the investigator will evaluate the results and your medical history to see if you are eligible 
for the trial.  If you are eligible, you will take abemaciclib twice daily by mouth in combination with 
fulvestrant. Fulvestrant will be injected into your muscle . Abemacilib and Fulvestrant will be 
administered for as long you tolerate the treatment, achieve maximum response per investigator’s 
assessment, or until your cancer gets worse. If your cancer comes back again during the course of 
treatment, a fresh biopsy will be obtained if clinically feasible. Prior to surgery and within 30 days of 
your last dose of treatment, you will be evaluated by your treating investigator for safety assessments, 
which will include physical exam, laboratory tests, and review of any new or ongoing symptoms. After 
the last treatment with Abemaciclib and Fulvestrant, you will undergo surgery as the standard of care. 
The surgical pathology will be examined to see if there is any residual cancer or not. 
 
This study also includes additional research studies, often called a correlative study, where extra blood 
will be collected to test for ctDNA (circulating tumor DNA), which are fragmented DNA that travel the 
bloodstream.  This test is to have a better understanding on how or why some tumor cells is not 
affected by hormone therapy (endocrine resistance), how abemaciclib overcomes endocrine 
resistance as well as the mechanism of response or resistance to abemaciclib and to identify other 
relevant biomarkers (genes that may be an endocrine resistance indicator). The ctDNA collection will 
occur at screening, every 3 months while on treatment and every 6 months (after definitive surgery) 
until the end of the study at 5 years. In addition to the collection of your blood, the correlative study will 
also be looking at your collected tissue at screening, during your regularly scheduled surgery and 
tissue that is collected if your cancer has gotten worse. Next generation sequencing (NGS) testing will 
be done on these tissue samples.    
 
Expected Duration 
Participation will be every two weeks for clinic visits and treatment for the first cycle and every four 
weeks for subsequent cycles as long as you are in the study. Each cycle is 28 days. There will be MRI 
imaging of your breast every 12 weeks from your first dose of therapy during the treatment phase. The 
duration of treatment and the duration of visit to your treating physician can vary anywhere from two to 
four hours.  You will remain on study as long as you show a best response per treating investigator’s 
clinical judgement, the disease is controlled and you are able to tolerate treatment. Response to the 
treatment will be made by the treating physician by clinical assessment and comparing the size of the 
tumor before and after treatment.  Best response will be defined as the smallest reduction in the size 
of the tumor prior to surgery. After you come off treatment, you will have surgery, and after surgery, 
you will be followed for ctDNA blood collection every 6 months for up to 5 years.  
 
Risks of Participation 
The more notable risks of participation include side effects associated with the study drugs including 
fatigue, nausea/vomiting, low blood count with increased risk of infection or bleeding. Should there be 
a breach in confidentiality of your data, there is a slight risk that your private medical information could 
be shared with individuals who are not members of the study team. 
 
Benefits to Participants 
Taking part in this study may or may not make your health better. While researchers hope the 
combination of abemaciclib and fulvestrant controls the disease longer than the standard (usual) 
treatment, there is no proof of this yet. 
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Benefits to Others or Society 
This study will help researchers learn more about the combination of abemaciclib and fulvestrant and it 
is hoped that this information will help in the treatment of future patients with breast cancer.  
 
Alternative Procedures or Treatments 
If you decide not to participate, or if you withdraw from this study before it is completed, your other 
choices may include: 
 
Getting no treatment 
 
Getting standard treatment for your condition without being in a study such as surgery, or 
treatments such as Fulvestrant and CDK4/6 inhibitors, drugs that restore a protein which prevents 
cancer cells from growing 
 
Getting a different experimental treatment/taking part in another study. 
 
 
WHY IS THIS RESEARCH STUDY BEING DONE? 
The main reason for you to take part in this study is that by treating you, the following research question 
could be answered:  
 
Does the combination of abemaciclib plus fulvestrant improve a pathologic complete response (a 
complete response is defined as the absence of breast cancer in the breast and/or the axillary (a 
person’s armpit) lymph nodes in the surgical specimen) in Hormone Receptor positive patients whose 
breast cancer came back in  the breast and not spread to other distant organs (localized non-metastatic 
breast cancer) and demonstrate molecular resistance to endocrine therapy after being treated with 
adjuvant hormone therapy.  
 
“Investigational/Experimental” means that the drugs (abemaciclib plus fulvestrant) being tested have not 
been approved for the use described in this study by the United States Food and Drug Administration 
(FDA).  Both of the study drugs, abemaciclib and fulvestrant, are FDA approved drugs for indications 
other than as being used in this study. Both Abemaciclib and Fulvestrant are approved for patients with 
mestastic (cancer that has spread from the site of origin to other parts of the body) breast cancer whose 
cancer has worsened.  
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?   
Approximately 32 participants will take part in the research at UCI.  
 
AM I ELIGIBLE TO PARTICIPATE IN THIS STUDY?  
Please note this may not be a complete list of eligibility criteria. We have included a few examples of 
study criteria to help you better understand how your eligibility in the study will be determined; your study 
team will go through the study eligibility criteria with you to verify if you qualify for participation in this 
study. 
 
Inclusion Requirements 
You can participate in this study if you  
 
Are at least 18 years of age or older 
 
Must have Stage I, Stage II and stage III breast cancer  
 
Must be post-menopausal 
 
Able to swallow oral medications  
 
Must be able to sign a written informed consent, are reliable, willing to be available for the 
duration of the study and are willing to follow study procedures 
 
Exclusion Requirements  
You cannot participate in this study if you  
 
Have Stage IV metastatic breast cancer 
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
Are premenopausal

Have HER2 negative or triple negative breast cancer

Prior treatment with either abemaciclib (or similar compound) and/or fulvestrant

Have a history of any other cancer (except for non-melanoma skin cancer or carcinoma in situ of
the cervix) that has not been in remission for the past three years or have not received a stem-
cell transplant
HOW LONG WILL THE STUDY GO ON? 
This study will consist of a screening period of up to 28 days.  You will take abemaciclib twice daily by 
mouth in combination with Fulvestrant, which will be injected into your muscle for as long you respond to 
treatment, can tolerate the treatment or until your cancer gets worse.  After treatment is complete, you 
will have surgery as standard of care.  After your surgery, you will be followed every 6 months for ctDNA 
blood collection for up to 5 years.  
WHAT PROCEDURES ARE INVOLVED WITH THIS STUDY? 
Before you can participate in the main part of the study... 
You will need to have “screening” exams, tests or procedures.  The screening process helps the 
researchers decide if you meet the study requirements listed below and must be done within 28 days 
before starting treatment.  The screening procedures include: 

We will review your medical history, including your cancer history

We will do a physical examination.  It will also include a recording of your height and weight.

We will collect blood for safety tests. This is done as part of your regular cancer care.

We will collect blood for ctDNA analysis. ctDNA is portion of your DNA from your tumor that is
circulating in your bloodstream. The amount of blood collected will be about 17 ml (approximately
3.5 teaspoons).

We will review any medications that you take, including over-the-counter drugs vitamins, and
herbal products.

We will ask how you are feeling and if your level of activity has changed.

We will look at places where your tumors can come back. We will use one of the tests described
below. Your study doctor will decide what test is best for you. This is being done as part of your
regular cancer care. These images will include your chest, abdomen and pelvis.
o
Computed Tomography (CT) Scan: This test uses a small amount of radiation (x-ray) to
take pictures of the inside of your body. It can show a cross section, like a thin “slice” of
your body, or it can show the body tissues and structures in “3-D”. For this test, the study
doctor or staff may give you a contrast dye, either by mouth or injected into a vein with a
needle. The study doctor or staff can tell you more about the contrast dye.
o
Magnetic Resonance Imaging (MRI) Scan: This test uses powerful magnets and radio
waves to make pictures of body tissues and structures. During an MRI, you must lie on
your back in the MRI scanner without moving. The inside of the MRI scanner is a tight
space. You may have a contrast dye given by mouth or injected into a vein with a needle.
The study doctor or staff can tell you more about the contrast dye.

After you provide your consent to participate in this study, your study doctor will arrange for a
sample of your cancer to be evaluated for molecular testing. This can be taken from tissue that
was obtained from a previous biopsy/surgery or it can be a new biopsy. This tissue will be utilized
for the correlative portion of the trial.
During the main part of the study... 
If the screening exams, tests and/or procedures show that you can continue to be in the study, and you 
choose to take part, then you will have the following procedures and tests done.  You will take 
abemaciclib twice daily by mouth in combination with Fulvestrant that will be injected into your muscle for 
as long you tolerate the treatment, a maximal response is obtained or until your cancer gets worse.  After 
the treatment phase is over, you will have surgery as the standard of care.  
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The main study tests and procedures include: 
 
We will review your medical history, including your cancer history. 
 
We will do a physical examination. This also includes a recording of your weight. 
 
We will review any medications that you take, including over-the-counter drugs vitamins, and 
herbal products. 
 
We will collect blood for safety tests. This is being done as part of your regular cancer care.  
 
We will collect blood for ctDNA analysis  every three months while on treatment and then every 6 
months after surgery until the end of the study at five years. The amount of blood collected each 
time will be about 17 ml (approximately 3.5 teaspoons).  
 
We will ask how you are feeling and if your level of activity has changed. 
o You will have an MRI scan of your breast every 12 weeks after your first dose of 
treatment. MRI will be done every 12 weeks while on the treatment. The size of the tumor 
in the MRI prior to treatment and after treatment will determine the best response. 
Magnetic Resonance Imaging (MRI) Scan: This test uses powerful magnets and radio 
waves to make pictures of body tissues and structures. During an MRI, you must lie on 
your back in the MRI scanner without moving. The inside of the MRI scanner is a tight 
space. You may have a contrast dye given by mouth or injected into a vein with a needle. 
The study doctor or staff can tell you more about the contrast dye. 
 
After you complete the main part of the study  
You will undergo the following visits: 
 
Off Treatment Visit 
If you finish treatment or decide to stop taking part in the study, we will contact you to come in for a follow 
up visit. This will take place within 30 days after you have finished taking the study drug and prior to 
surgery. The procedures in this visit include: 
 
We will review your medical history, including your cancer history. 
 
We will do a physical examination. This also includes a recording of your weight. 
 
We will collect blood for safety tests. This is being done as part of your regular cancer care. 
 
We will collect blood for ctDNA analysis  ctDNA is portion of your DNA from your tumor that is 
circulating in your bloodstream.  
 
We will collect a fresh biopsy if your cancer has gotten worse and if clinically feasible. Some of 
the tissue from this biopsy will be used for the correlative portion of the trial. 
 
We will ask how you are feeling and if your level of activity has changed. 
 
We will review any medications that you take, including over-the-counter drugs vitamins, and 
herbal products. 
 
Surgery 
 
You will undergo surgery as part of your regular care even if you were not participating in this research 
study. Details will be explained by your treating physician. Some of the tissue from this surgery will be 
used for the correlative portion of the trial.   
 
Follow-up 
After you complete surgery, we will collect blood for ctDNA every 6 months until the end of the study at 5 
years.  
RETURN OF RESULTS  
You will not be provided any clinically relevant information that may pertain to your health.  
 
 
 
 
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WHAT ARE THE POSSIBLE SIDE EFFECTS OR RISKS RELATED TO THE STUDY? 
You may have side effects while on the study.  Everyone taking part in the study will be watched carefully 
for any side effects.  However, researchers don't know all the side effects that may happen.  Side effects 
may be mild or very serious.  The researchers may give you medicines to help lessen side effects.  Many 
side effects go away soon after you stop taking abemaciclib and Fulvestrant.  In some cases, side effects 
can be serious, long lasting, or may never go away.  In some cases side effects may result in death.  
 
You should talk to the research team about any side effects you experience while taking part in the 
study. 
 
Risks and side effects related to abemaciclib and Fulvestrant include those which are: 
 
Abemaciclib 
 
Safety information available (as of 26 September 2018) from 4299 patients with cancer and 328 healthy 
subjects who have taken abemaciclib has been reviewed. 
 
Abemaciclib given alone: 
 
Very Common (Reported in 10 or more out of 100 subjects) (greater than or equal to 10%) 
 
 
Loose stools (diarrhea) 
o The study team will discuss with you how to properly manage this side effect. You may be 
prescribed medicines to prevent this.  
 
Lack of energy (fatigue) 
 
Feeling sick to the stomach  
 
Vomiting  
 
Low appetite (decreased appetite) 
 
Decreased number of white blood cells count in the blood; this may make infections more likely to 
occur (neutropenia; leukopenia) 
 
Low red blood cell count in the blood that may make you feel more tired (anemia) 
 
Decreased number of platelets in the blood; this may cause bruising, difficulty with clotting of 
blood, or bleeding easily (thrombocytopenia) 
 
Dry mouth 
 
Inflammation or ulcers inside the mouth (stomatitis) 
 
Taste changes or bad taste in the mouth (dysgeusia) 
 
Hair loss (alopecia) 
 
Common (Reported in 1 or more but less than 10 out of 100 subjects) (greater than or equal to 1% 
but less than 10%) 
 
 
Decreased number of lymphocytes in the blood; this may make infections more likely to occur 
(lymphopenia). 
 
Inflammation of the lungs causing coughing and difficulty breathing (interstitial lung 
disease/pneumonitis). 
 
Very often, increases in creatinine levels, a substance in the blood that measures kidney function, were 
noted by laboratory testing. While abemaciclib does not decrease kidney function, creatinine increases 
may indicate the need for other tests of kidney function. 
 
Other chemotherapy drugs and other forms of treatment will also have their own, often unique, side 
effects that should be taken into account when considering the likely effects of the treatment combination 
as a whole. 
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Abemaciclib in combination with fulvestrant was given to 441 patients. Patients treated with this 
combination may experience the side effects listed for abemaciclib given alone. In addition, other side 
effects that occurred in these patients included: 
 
 
Very Common (Reported in 10 or more out of 100 subjects) (greater than or equal to 10%) 
 
 
Infections 
 
An increase in liver enzymes  made by the liver (alanine aminotransferase increased,  aspartate 
aminotransferase increased) 
 
Itching (pruritus) 
 
Dizziness 
 
Rash 
 
Muscle weakness 
 
Common (Reported in 1 or more but less than 10 out of 100 subjects) (greater than or equal to 1% 
but less than 10%) 
 
 
Dry skin 
 
Increased watering of eyes (lacrimation increased) 
 
Blood clots in veins (venous thromboembolic events) 
 
Fulvestrant 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
You may need immediate medical treatment if you experience any of the following side effects: 
 
Allergic (hypersensitivity) reactions, including swelling of the face, lips, tongue, and/or throat that 
may be signs of anaphylactic reactions 
 
Thromboembolism (increased risk of blood clots) 
 
Inflammation of the liver (hepatitis) 
 
Liver failure 
 
Tell your doctor, pharmacist, or nurse if you notice any of the following side effects: 
 
Very Common side effects (may affect more than 1 in 10 people) (greater than or equal to 10%) 
 
 
Injection site reactions, such as pain and/or inflammation 
 
Abnormal levels of liver enzymes (in blood tests) 
 
Nausea (feeling sick) 
 
Weakness, tiredness 
 
Joint and musculoskeletal pain 
 
Hot flushes 
 
Skin rash 
 
Allergic (hypersensitivity) reactions, including swelling of the face, lips, tongue, and/or throat 
 
All other side effects: 
 
Common side effects (may affect up to 1 in 10 people) (greater than or equal to 1% but less than 
10%) 
 
 
Headache 
 
Vomiting, diarrhea, or loss of appetite 
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 
Urinary tract infections 
 
Back pain 
 
Increase of bilirubin (bile pigment produced by the liver) 
 
Thromboembolism (increased risk of blood clots) 
 
Decreased levels of platelets (thrombocytopenia) 
 
Vaginal bleeding 
 
Lower back pain irradiating to leg on one side (sciatica) 
 
Sudden weakness, numbness, tingling, or loss of movement in your leg, especially on only one 
side of your body, sudden problems with walking or balance (peripheral neuropathy) 
 
Uncommon side effects (may affect up to 1 in 100 people) (less than 1%) 
 
 
Thick, whitish vaginal discharge and candidiasis (infection) 
 
Bruising and bleeding at the site of injection 
 
Increase of gamma-GT, a liver enzyme seen in a blood test 
 
Inflammation of the liver (hepatitis) 
 
Liver failure 
 
Numbness, tingling and pain 
 
Anaphylactic reactions 
 
 
Blood draw:  Removing blood by a needle may cause temporary pain, bruising, bleeding, swelling, 
dizziness, and on rare instances fainting or infection.  
 
Unknown risks: There may be risks related to the research that we do not know about yet.  However, 
you will be informed of any additional risks to which you may be exposed, and any changes that are 
made to the study, as a result of any newly-identified risks.  
 
Reproductive Risks: You should not get pregnant while in this study. Abemaciclib used in this study 
could harm an unborn baby. Check with the researchers about what types of birth control, or pregnancy 
prevention, to use while in this study. 
 
You should also not breastfeed a baby while in this study, as the the study drug used in this study could 
harm a newborn baby. 
 
If you are a male, you should not father a baby while on this study.   
 
If you or your partner does become pregnant during the study, you should contact the researchers 
immediately.   
 
 
WILL I BE PAID FOR TAKING PART IN THIS STUDY?  
You will not be compensated for your participation in this research study. 
 
Reimbursement  
You will not be reimbursed for any out of pocket expenses, such as parking or transportation fees.  
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?  
The study supporter (Eli Lilly and Company) will supply abemaciclib tablets at no cost while you take part 
in the study. You and/or your health plan/insurance will need to cover the cost of the injection of 
Fulvestrant. Any additional research-related tests, procedures or visits will also be provided at no cost 
while you take part in this study. 
 
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Most of the tests, procedures, and/or drugs provided to you are routinely used to treat your illness. You 
would receive these tests, procedures, and/or drugs even if you were not participating in this study. You 
and /or your health plan/insurance will need to pay for this routine care. You will also be responsible for 
any co-payments or deductibles required by your insurance. Some health plans/insurance companies will 
not pay the costs associated with these tests, procedures, and/or drugs. Financial counseling and 
itemized cost estimates are available upon request. 
 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY?  
It is important that you promptly tell the researchers if you believe that you have been injured because of 
taking part in this study.  You can tell the researcher in person or call him/her at the number listed at the 
top of this form. 
 
If you are injured as a result of being in this study, UCI will provide necessary medical treatment. The 
costs of the treatment may be covered by the University of California or billed to you or your insurer just 
like other medical costs, depending on a number of factors. The University does not normally provide any 
other form of compensation for injury.  For more information about this, you may call UCI Human 
Research Protections (949) 824-6068 or (949) 824-2125 or by e-mail at IRB@research.uci.edu 
 
 
WHAT HAPPENS IF I WANT TO STOP TAKING PART IN THIS STUDY?  
You are free to withdraw from this study at any time. If you decide to withdraw from this study, you 
should notify the research team immediately. The research team may also end your participation in 
this study if you do not follow instructions, miss scheduled visits, the study sponsor decides to stop the 
study or your safety and welfare are at risk. 
 
If you experience any of the side effects listed above, if your health worsens, or if you are injured during 
the research, you may need to be withdrawn from the study, even if you would like to continue.  The 
research team will make this decision and let you know if it is not possible for you to continue.  The 
decision may be made to protect your safety and welfare, or because the research plan does not allow 
people who develop certain conditions to continue to participate.  
 
If you withdraw or are removed from the study, the researcher may ask you to return for a final visit and 
follow up with you in the clinic or by phone at least every 6 months to check on your health status.  
 
1.  If you elect to withdraw or are withdrawn from this FDA-regulated research study, the data 
collected from your participation in this study must remain in the trial database in order for the 
study to be scientifically valid. 
 
 
HOW WILL INFORMATION ABOUT ME AND MY PARTICIPATION BE KEPT? 
Subject Identifiable Data 
Some identifiable information collected about you will be removed and replaced with a code. A list linking 
the code and your identifiable information will be kept separate from the research data. 
 
Data Storage 
Research data will be maintained in paper format in a secure location at UCI. 
 
Research data will be stored electronically on a secure network in an encrypted file with password 
protection. 
 
Data Retention 
Research data will be kept on file until three years after the completion of the final study report of this 
study.  
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WHO WILL HAVE ACCESS TO MY STUDY DATA? 
The research team, authorized UCI personnel, and regulatory entities such as the Food and Drug 
Administration (FDA) and the Office of Human Research Protections (OHRP), may have access to your 
study records to protect your safety and welfare. 
 
While the research team will make every effort to keep your personal information confidential, it is 
possible that an unauthorized person might see it.  We cannot guarantee total privacy. 
 
Future Research Use  
Your information may be used for future research still to be planned. Possible future research studies 
may include, for example: 
 
Studying factors associated with benefit from the study medication 
 
You will not be informed about any of the specific research studies that might be conducted with your 
information. This means that your information could be used in research in which you might not have 
chosen to participate (i.e. without your additional consent). 
 
Sharing for Future Research 
Any information shared for future research will not include your name or other personal identifying 
information. 
 
ClinicalTrials.gov ClinicalTrials.gov is a Web site that provides information about clinical trials.  A 
description of this clinical trial will be available on http://www.clinicaltrials.gov/, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will include a 
summary of the results. You can search this Web site at any time.  
 
Clinical Trials Reporting Program  
UCI’s NCI-Designated Cancer Center or the Sponsor registers National Cancer Institute (NCI)-supported 
clinical trials with NCI though their Clinical Trials Reporting Program (CTRP) to provide study related 
information. The data provided will include the following identifiable information that may identify you: 
birth month/year and five-digit zip code.  NCI uses the data to manage and enhance the nation’s 
investment in cancer research. 
 
Investigator Financial Conflict of Interest 
No one on the study team has a disclosable financial interest related to this research project. 
 
Genetics 
In the event of an unexpected breach of confidentiality, a federal law called the Genetic Information Non-
Discrimination Act (GINA) will help protect you from health insurance or employment discrimination 
based on genetic information obtained about you. In California, state law (CalGINA) requires that 
employers with 5 or more employees may not use your genetic information, obtained from this research 
when making a decision to hire, promote, or fire you or when setting the terms of your employment. 
However, these laws do not protect you against discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance.  
 
If you would like more information about the federal GINA law go to: 
http://www.genome.gov/Pages/PolicyEthics/GeneticDiscrimination/GINAInfoDoc.pdf or CalGINA: 
http://www.leginfo.ca.gov/pub/11-12/bill/sen/sb_0551-0600/sb_559_bill_20110906_chaptered.pdf 
 
 
 
 
 
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ARE THERE OTHER ISSUES TO CONSIDER IN DECIDING WHETHER TO PARTICIPATE IN THIS 
STUDY?  
Use of Biospecimens 
Biospecimens (such as blood, tissue, or saliva) collected from you for this study and/or information 
obtained from your biospecimens may be used in this research or other research, and shared with other 
organizations. You will not share in any commercial value or profit derived from the use of your 
biospecimens and/or information obtained from them. 
 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
If you have any comments, concerns, or questions regarding the conduct of this research, please contact 
the research team listed at the top of this form. 
 
A 24-hour number is also listed on the top of this form to report any health concerns or unanticipated 
problems you may experience after normal hours or on weekends. 
 
If you wish to ask questions about the study or your rights as a research participant to someone other 
than the researchers or if you wish to voice any suggestions, problems or concerns you may have about 
the study, please contact the UCI Institutional Review Board by phone, (949) 824-6068 or (949) 824-
2125, by e-mail at IRB@research.uci.edu or at 160 Aldrich Hall, Irvine, CA 92697-7600.  
 
What is an IRB?  An Institutional Review Board (IRB) is a committee made up of scientists and non-
scientists.  The IRB’s role is to protect the rights and welfare of human subjects involved in 
research.  The IRB also assures that the research complies with applicable regulations, laws, and 
institutional policies.  
 
HOW DO I AGREE TO PARTICIPATE IN THIS STUDY?  
You should not sign and date this consent form until all of your questions about this study have been 
answered by a member of the research team listed at the top of this form. You will be given a copy of this 
signed and dated consent form, and the attached “Experimental Subject’s Bill of Rights” to keep. 
Participation in this study is voluntary.  You may refuse to answer any question or discontinue your 
involvement at any time without penalty or loss of benefits to which you might otherwise be entitled.  
Your decision will not affect your future relationship with UCI or your quality of care at the UCI Medical 
Center.   
 
If, during the course of this study, significant new information becomes available that may relate to your 
willingness to continue to participate, this information will be provided to you by the research team listed 
at the top of the form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Your signature below indicates you have read the information in this consent form and have had a 
chance to ask any questions you have about this study.   
 
Note: As the research described in this form involves your protected health information (PHI), 
you will be asked to sign separate UC HIPAA Research Authorization form for the use of your 
PHI.  
 
I agree to participate in the study.  
 
___________________________________________________ 
 
__________________ 
 Subject Signature  
 
 
 
 
 
 
Date 
 
___________________________________________________ 
 Printed Name of Subject   
 
 
___________________________________________________ 
 
__________________ 
Signature of Person Obtaining Informed Consent 
 
 
Date 
(For research that is greater than minimal risk, this individual must be listed on Page 1 of this consent) 
 
___________________________________________________ 
 
 Printed Name of Person Obtaining Informed Consent  
 
 
 
A witness signature is required on this consent form only if: (Researchers: check which one applies) 
 
IMPORTANT! If no witness signature is required, this witness signature section of the consent form may be 
left blank. 
 
Consent is obtained from the subject via the Short Form process, as approved by the IRB. 
The subject has decision-making capacity, but cannot read, write, talk or is blind.  
The subject’s guardian/legally authorized representative (LAR) cannot read, write, talk or is blind. 
The IRB specifically mandated a witness signature for this study (e.g., high risk and/or invasive  
     research procedures). 
 
For the witness:  
I confirm that the information in this consent form was accurately explained to and understood by the 
subject or legally authorized representative and that informed consent was given freely. 
 
___________________________________________________ 
__________________ 
Witness Signature 
 
 
 
 
 
 
    
 Date 
Note: The witness must be impartial (i.e. not a member of the subject’s family, not a member of the study team).   
 
___________________________________________________ 
 
Printed Name of Witness 
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UNIVERSITY OF CALIFORNIA, IRVINE 
Experimental Subject's Bill of Rights 
 
The rights listed below are the right of every individual asked to participate in a research study. 
You have the right:  
 
1. To be told about the nature and purpose of the study.  
 
2. To be told about the procedures to be followed in the research study, and whether any of the 
drugs, devices, or procedures is different from what would be used in standard practice.  
 
3. To receive a description of any side effects, discomforts, or risks that you can reasonably expect 
to occur during the study.  
 
4. To be told of any benefits that you may reasonably expect from the participation in the study, if 
applicable.  
 
5. To receive a description of any alternative procedures, drugs, or devices that might be helpful, 
and their risks and benefits compared to the proposed procedures, drugs or devices.  
 
6. To be told of what sort of medical treatment, if any, will be available if any complications should 
arise.  
 
7. To be given a chance to ask any questions concerning the research study both before agreeing 
to participate and at any time during the course of the study.  
 
8. To refuse to participate in the research study. Participation is voluntary. You may refuse to 
answer any question or discontinue your involvement at any time without penalty or loss of 
benefits to which you might otherwise be entitled.  Your decision will not affect your right to 
receive the care you would receive if you were not in the experiment.   
 
9. To receive a copy of the signed and dated written consent form and a copy of this form.  
 
10. To be given the opportunity to freely decide whether or not to consent to the research study 
without any force, coercion, or undue influence.  
------------------------------------------------------- 
 
If you have any concerns or questions regarding the research study you should contact the research 
team listed at the top of the consent form. 
 
If you are unable to reach a member of the research team and have general questions, or you have 
concerns or complaints about the research study, research team, or questions about your rights as a 
research subject, please contact the UCI’s Human Research Protections unit in the Office of Research 
by calling (949) 824-6068 or (949) 824-2125 Monday – Friday, 8 am – 5 pm; or by e-mail at 
IRB@research.uci.edu; or by writing us at 160 Aldrich Hall, Irvine, CA 92697-7600. 
 
 
 
 
 
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UC Irvine HIPAA Research Authorization 2014 
UCI IRB#   
2020-5660  
 
 
University of California Irvine Health 
Permission to Use Personal Health Information for Research 
Study Title (or IRB Approval Number if study title may breach subject’s privacy): 
UCI 18-79: A Phase II Open Label Trial of Neo-Adjuvant Abemaciclib with Fulvestrant 
in Patients Who Develop Localized Recurrence While on Adjuvant Endocrine Therapy 
with Molecular Evidence of Endocrine Resistance  
Principal Investigator Name: 
Ritesh Parajuli, MD 
Sponsor/Funding Agency (if funded): 
UC Irvine  
A. What is the purpose of this form? 
State and federal privacy laws protect the use and release of your health information. 
Under these laws, the University of California or your health care provider cannot 
release your health information for research purposes unless you give your permission. 
Your information will be released to the research team which includes the researchers, 
people hired by the University or the sponsor to do the research and people with 
authority to oversee the research. If you decide to give your permission and to 
participate in the study, you must sign this form as well as the Consent Form. This form 
describes the different ways that health care providers can share your information with 
the researcher, research team, sponsor and people with oversight responsibility. The 
research team will use and protect your information as described in the attached 
Consent Form. However, once your health information is released by UC Irvine Health 
it may not be protected by the privacy laws and might be shared with others. If you 
have questions, ask a member of the research team. 
B. What Personal Health Information will be released? 
If you give your permission and sign this form, you are allowing your health care 
provider to release the following medical records containing your Personal Health 
Information. Your Personal Health Information includes health information in your 
medical records, financial records and other information that can identify you. 
 
 


UC Irvine HIPAA Research Authorization 2014 
  Entire Medical Record 
  Ambulatory Clinic Records 
  Progress Notes 
  Other Test Reports 
  Other (describe): 
 
__________________________ 
(Description of Other Health Information) 
  Lab & Pathology  
        Reports 
     Dental Records 
     Operative Reports 
     Discharge Summary 
     Consultations 
 Emergency Department  
    Records 
 Financial Records 
 Imaging Reports 
 History & Physical Exams 
 Psychological Tests 
C. Do I have to give my permission for certain specific uses? 
Yes. The following information will only be released if you give your specific permission 
by putting your initials on the line(s). 
 
I agree to the release of information pertaining to drug and alcohol abuse, 
diagnosis or treatment. 
 
I agree to the release of HIV/AIDS testing information. 
 
I agree to the release of genetic testing information. 
 
I agree to the release of information pertaining to mental health diagnosis or 
treatment. 
D. Who will disclose and/or receive my Personal Health Information? 
Your Personal Health Information may be shared with these people for the following 
purposes: 
1. To the research team for the research described in the attached Consent Form; 
2. To others at UC with authority to oversee the research 
3. To others who are required by law to review the quality and safety of the research, 
including: U.S. government agencies, such as the Food and Drug Administration 
or the Office of Human Research Protections, the research sponsor or the 
sponsor’s representatives, or government agencies in other countries. 
E. How will my Personal Health Information be shared for the research? 
If you agree to be in this study, the research team may share your Personal Health 
Information in the following ways: 
1. To perform the research 
2. Share it with researchers in the U.S. or other countries; 
3. Use it to improve the design of future studies; 
4. Share it with business partners of the sponsor; or 
5. File applications with U.S. or foreign government agencies to get approval for 
new drugs or health care products. 


UC Irvine HIPAA Research Authorization 2014 
F. Am I required to sign this document? 
No, you are not required to sign this document. You will receive the same clinical care 
if you do not sign this document. However, if you do not sign the document, you will not 
be able to participate in this research study. 
G. Optional research activity 
If the research I am agreeing to participate in has additional optional research activity 
such as the creation of a database, a tissue repository or other activities, as explained 
to me in the informed consent process, I understand I can choose to agree to have my 
information shared for those activities or not. 
 I agree to allow my information to be disclosed for the additional optional 
research activities explained in the informed consent process. 
H. Does my permission expire? 
This permission to release your Personal Health Information expires when the 
research ends and all required study monitoring is over. 
I. Can I cancel my permission? 
You can cancel your permission at any time. You can do this in two ways. You can 
write to the researcher or you can ask someone on the research team to give you a 
form to fill out to cancel your permission. If you cancel your permission, you may no 
longer be in the research study. You may want to ask someone on the research team if 
canceling will affect your medical treatment. If you cancel, information that was already 
collected and disclosed about you may continue to be used for limited purposes. Also, 
if the law requires it, the sponsor and government agencies may continue to look at 
your medical records to review the quality or safety of the study. 
J. Signature 
Subject 
If you agree to the use and release of your Personal Health Information, please print 
your name and sign below. You will be given a signed copy of this form. 
 
 
 
 
 
 
 
 
 
 
Subject’s Name (print)—required 
 
 
 
 
 
 
 
 
 
 
Subject’s Signature 
__________________ 
Date 


UC HIPAA Research Authorization 2014 
Parent or Legally Authorized Representative 
If you agree to the use and release of the above named subject’s Personal Health 
Information, please print your name and sign below. 
 
 
 
 
 
 
 
 
 
 
Parent or Legally Authorized Representative’s Name 
(print) 
 
 
 
 
 
Relationship to Subject 
 
 
 
 
 
 
 
 
 
 
 
Parent or Legally Authorized Representative’s 
Signature 
 
 
 
 
 
Date
Witness 
If this form is being read to the subject because s/he cannot read the form, a 
witness must be present and is required to print his/her name and sign here: 
 
 
 
 
 
 
 
 
 
 
Witness’ Name (print) 
 
 
 
 
 
 
 
 
 
 
Witness’ Signature 
 
 
 
 
 
Date