Pilot Clinical Trial of Treatment With LY3023414 and Prexasertib to Inhibit Homologous Recombination (HR) in Patients With Chemotherapy-Pretreated Metastatic Triple Negative Breast Cancer (Amendment 1)
Phase: PHASE2
Conditions: Triple Negative Breast Cancer
Sponsor: Baylor Research Institute

 
 
 
Page 1 of 52 
 
RESEARCH PROTOCOL 
PILOT CLINICAL TRIAL OF TREATMENT WITH LY3023414 AND 
PREXASERTIB TO INHIBIT HOMOLOGOUS RECOMBINATION (HR) IN 
PATIENTS WITH CHEMOTHERAPY-PRETREATED METASTATIC TRIPLE 
NEGATIVE BREAST CANCER 
 
Protocol Number: 
018-745 
 
 
FDA IND Number: 
141498 
 
 
Date: 
November 16, 2018  
Amendment 1 
December 02, 2020  
 
 
 
 
Principal Investigator: 
Joyce O’Shaughnessy, MD 
 
Celebrating Women Chair in Breast Cancer 
Research, 
 
Baylor Sammons Cancer Center/ 
 
Texas Oncology 
 
Co-Chair, Breast Cancer Research Program, 
 
The US Oncology Network 
 
3410 Worth Street, Suite 400 
 
Dallas, TX 75246 
 
(214) 370-1795 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Page 2 of 52 
SITE INVESTIGATOR SIGNATURE PAGE 
The signature below constitutes the approval of this protocol entitled “Pilot clinical trial of 
treatment with LY3023414 and prexasertib to inhibit homologous recombination (HR) in 
patients with chemotherapy-pretreated metastatic triple negative breast cancer”, and provides the 
necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
 
Site Investigator: 
 
 
 
Signed: _____________________________________ Date: _________________ 
 
 
Name:______________________________________ 
 
 
 
 

 
Page 3 of 52 
 
ABBREVIATIONS 
Abbreviation 
Term 
5-FU 
5-fluorouracil 
AE 
Adverse event 
AKT 
Protein kinase B 
ALT 
Alanine aminotranserase 
ANC 
Absolute neutrophil count 
ASCO 
American society of clinical oncology 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under the curve 
BC 
Breast cancer 
BID 
bis in die; twice a day 
BRCA 
Breast cancer susceptibility gene 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CHK1 
Checkpoint kinase 1 
CI 
Confidence interval 
CL 
Drug clearance 
Cmax 
Maximum (or peak) serum concentration 
CMP 
Complete metabolic profile 
CO2 
Carbon dioxide 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CTEP 
Cancer Therapy Evaluation Program 
CR 
Complete response 
CRF 
Case report form 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DLCO 
Diffusing capacity 
DNA 
Deoxyribonucleic acid 
ECG  
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
ER 
Estrogen receptor 
FDA 
Food and Drug Administration 
FEC/T 
5-fluorouracil, epirubicin, cyclophosphamide plus docetaxel 
FFPE 
Formalin-fixed paraffin embedded 

 
Page 4 of 52 
G-CSF 
Granulocyte colony stimulating factor 
gm 
Gram  
HbA1c 
Hemoglobin A1c 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HR 
Homologous recombination 
hr 
Hour 
HRD 
Homologous recombination deficiency 
IC50 
Concentration of an inhibitor where the response (or binding) is 
reduced by half 
ID 
Identification  
IM 
Internal mammary 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IV 
Intravenous  
JAK 
Janus kinase 
L 
Liter  
LFU 
Lost to follow up 
LN 
Lymph node 
m 
Meter  
MAPK 
Map kinase 
Mg 
Magnesium 
mg 
Milligram 
mm 
Millimeter 
MBC 
Metastatic breast cancer 
metTNBC 
Metastatic TNBC 
mg 
Milligram 
mL 
Milliliter 
mOsm 
Milliosmole; 1/1,000 of an osmole 
MRI 
Magnetic resonance imaging 
ms 
Millisecond 
mTOR 
mechanistic target of rapamycin 
mTOR[1] or [2] 
target of rapamycin complex [1 or 2] 
ng 
Nanogram 
NGS 
Next generation sequencing 
NHEJ 
Non-homologous end-joining 
NSCLC 
Non-small cell lung cancer 
PARP 
Poly (ADP-ribose) polymerase 
P 
Phosphorus 
PI 
Principal Investigator 
PI3K 
Phosphatidylinositol-4,5-bisphosphate 3-kinase 

 
Page 5 of 52 
PD 
Progressive Disease or Pharmacodynamics 
PgR 
Progesterone receptor 
PK 
Pharmacokinetics 
PO 
per os; by mouth (orally) 
PR 
Partial response 
PS 
Performance scale 
QD 
quaque die; each day; once daily 
QT 
Measure between Q wave and T wave in the heart's electrical 
cycle 
QTcF 
QT corrected for HR using Fridericia's method 
RPPA 
Reverse phase protein array 
SAE 
Serious adverse event 
SC 
Supraclavicular 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SOP 
Standard operating procedure 
STAT 
Signal transducer and activator of transcription 
TEAE 
Treatment-emergent adverse events 
TK 
Toxicokinetics 
TNBC 
Triple negative breast cancer 
ULN 
Upper limits of normal 
Vss 
Volume of distribution at steady-state 
WLN 
Within normal limits 
 

 
Page 6 of 52 
Table of Contents 
ABBREVIATIONS .................................................................................................................................... 3 
SYNOPSIS ................................................................................................................................................ 9 
PART I – CLINICAL TRIAL PROTOCOL ................................................................................................ 13 
1 
INTRODUCTION ............................................................................................................................. 13 
1.1 
BACKGROUND ON TRIPLE NEGATIVE BREAST CANCER ........................................................................ 13 
1.2 
HOMOLOGOUS RECOMBINATION DEFICIENCY IN BREAST CANCER ...................................................... 13 
1.3 
LY3023414........................................................................................................................................ 14 
1.4 
PREXASERTIB (FORMERLY LY2606368) ............................................................................................ 14 
1.5 
LY3023414 AND PREXASERTIB IN COMBINATION .............................................................................. 15 
1.6 
EXCEPTIONAL RESPONDER CLINICAL HISTORY AND TUMOR MOLECULAR ALTERATIONS .................... 15 
1.7 
RATIONALE ......................................................................................................................................... 16 
2 
TRIAL OBJECTIVES ...................................................................................................................... 16 
2.1 
PRIMARY OBJECTIVES ......................................................................................................................... 16 
2.2 
SECONDARY OBJECTIVES .................................................................................................................... 16 
3 
STUDY DESIGN ............................................................................................................................. 16 
4 
SELECTION OF PATIENTS ........................................................................................................... 17 
4.1 
SAMPLE SIZE ....................................................................................................................................... 17 
4.2 
INCLUSION CRITERIA .......................................................................................................................... 17 
4.3 
EXCLUSION CRITERIA ......................................................................................................................... 18 
4.4 
REASONS OFF TREATMENT ................................................................................................................. 19 
4.5 
REASONS OFF STUDY ......................................................................................................................... 19 
5 
CONCOMITANT THERAPY ........................................................................................................... 20 
5.1 
DRUG-DRUG INTERACTIONS .............................................................................................................. 20 
5.1.1 
LY3023414 ....................................................................................................................................... 20 
5.1.2 
Prexasertib ......................................................................................................................................... 21 
6 
THERAPEUTIC AGENTS ............................................................................................................... 21 
6.1 
LY3023414........................................................................................................................................ 21 
6.1.1 
Formulation ....................................................................................................................................... 21 
6.1.2 
Storage and Stability ......................................................................................................................... 21 
6.1.3 
Preparation and Administration ......................................................................................................... 21 
6.1.4 
Pharmacokinetics .............................................................................................................................. 22 
6.1.5 
Adverse Effects ................................................................................................................................. 22 
6.2 
PREXASERTIB (LY2606368) .............................................................................................................. 23 
6.2.1 
Formulation ....................................................................................................................................... 23 
6.2.2 
Storage and Stability ......................................................................................................................... 23 
6.2.3 
Preparation and Administration ......................................................................................................... 24 
6.2.4 
Pharmacokinetics .............................................................................................................................. 24 
6.2.5 
Adverse Effects ................................................................................................................................. 24 
7 
INVESTIGATIONAL PLAN ............................................................................................................. 25 
7.1 
REGISTRATION PROCEDURES .............................................................................................................. 25 
7.2 
STUDY TREATMENT ADMINISTRATION ................................................................................................ 26 
7.2.1 
Premedications .................................................................................................................................. 26 
7.2.2 
Treatment Plan .................................................................................................................................. 26 
7.2.2.1 
LY3023414 ................................................................................................................... 27 
7.2.2.2 
Prexasertib .................................................................................................................. 27 
7.2.3 
Treatment Delay ................................................................................................................................ 28 
7.2.4 
Dose Modification for Toxicity ......................................................................................................... 28 
7.2.4.1 
LY3023414 Dose Modifications ................................................................................... 28 
7.2.4.2 
Prexasertib Dose Modifications .................................................................................. 29 
7.3 
TOXICITY ............................................................................................................................................ 31 
8 
SCHEDULE OF ASSESSMENTS .................................................................................................. 31 
8.1 
PRESTUDY ASSESSMENTS ................................................................................................................... 32 
8.2 
ASSESSMENTS DURING TREATMENT ................................................................................................... 33 
8.3 
OFF TREATMENT/END OF TREATMENT ASSESSMENTS .......................................................................... 34 
8.4 
FOLLOW UP ASSESSMENTS .................................................................................................................. 34 

 
Page 7 of 52 
8.5 
BLOOD SAMPLES FOR EXOME SEQUENCING ......................................................................................... 35 
8.6 
BIOPSIES ............................................................................................................................................. 35 
9 
SAFETY EVALUATIONS ............................................................................................................... 35 
9.1 
ADVERSE EVENTS ............................................................................................................................... 35 
9.2 
LABORATORY DATA ........................................................................................................................... 36 
10 
EFFICACY ASSESSMENTS (SOLID TUMOR) ............................................................................. 36 
11 
STATISTICAL CONSIDERATIONS ............................................................................................... 37 
11.1 
POPULATIONS FOR ANALYSIS............................................................................................................. 37 
11.1.1 
Analysis Populations ......................................................................................................................... 37 
11.1.2 
Patient Characteristics ....................................................................................................................... 37 
11.1.3 
Patient Disposition ............................................................................................................................ 37 
11.2 
HYPOTHESIS AND ENDPOINTS ............................................................................................................. 37 
11.3 
SAMPLE SIZE ....................................................................................................................................... 38 
11.4 
STATISTICAL METHODS ...................................................................................................................... 38 
PART II – PROCEDURES ........................................................................................................................ 39 
12 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 39 
12.1 
DEFINITIONS ....................................................................................................................................... 39 
12.1.1 
Adverse Event ................................................................................................................................... 39 
12.1.2 
Serious Adverse Event ...................................................................................................................... 39 
12.1.3 
Unexpected Adverse Event ............................................................................................................... 40 
12.2 
REPORTING ......................................................................................................................................... 40 
12.2.1 
Adverse Events .................................................................................................................................. 40 
12.2.2 
Serious Adverse Event ...................................................................................................................... 40 
12.2.3 
Discontinuation of Patient ................................................................................................................. 41 
12.3 
PREGNANCY ....................................................................................................................................... 41 
13 
PROTOCOL AND DATA DEVELOPMENT .................................................................................... 41 
13.1 
ETHICS ................................................................................................................................................ 41 
13.1.1 
Institutional Review Board ................................................................................................................ 41 
13.1.2 
Patient Informed Consent .................................................................................................................. 42 
13.1.3 
Confidentiality of Records ................................................................................................................ 42 
13.2 
STUDY RECORDS ................................................................................................................................. 42 
13.2.1 
Documentation .................................................................................................................................. 42 
13.2.2 
Case Report Form Procedures ........................................................................................................... 43 
13.3 
MODIFICATION OF PROTOCOL ............................................................................................................. 43 
14 
REFERENCES ................................................................................................................................ 44 
APPENDIX I 
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE), 
VERSION 4.0 .......................................................................................................... 46 
APPENDIX II 
SCHEDULE OF ASSESSMENTS .......................................................................... 47 
APPENDIX III 
ECOG PERFORMANCE STATUS SCALE ........................................................... 48 
APPENDIX IV 
RESEARCH BIOPSIES AND BLOOD COLLECTION .......................................... 49 
APPENDIX V 
PATIENT DIARY FOR LY3023414 ADMINISTRATION AND TREATMENT SIDE 
EFFECTS ................................................................................................................ 50 
 
 
 

 
Page 8 of 52 
 
 
In-Text Tables 
Table 1. 
Treatment schema ......................................................................................................27 
Table 2. 
LY3023414 Dose Reduction Levels ..........................................................................29 
Table 3. 
Prexasertib Dose Modification Levels .......................................................................30 
Table 4. 
Additional dose adjustment guidance for prexasertib ................................................30 
 

 
Page 9 of 52 
SYNOPSIS 
Summary:  
Seventy to 80% of breast cancers have a basal gene expression profile which is characterized by 
homologous recombination deficiency (HRD) and high proliferation. HRD leads to upregulation 
of the activity of the non-homologous end joining (NHEJ) error-prone pathway that repairs DNA 
double strand breaks, a process required for TNBC survival. The hypothesis of this pilot trial is 
that administration of LY3023414 and prexasertib will inhibit NHEJ in metastatic TNBC. A 
patient with an exceptional complete and durable response of her primary-refractory metastatic 
TNBC with PI3K pathway inhibition followed at disease progression by nab paclitaxel/cisplatin 
provides the clinical rationale for the present trial which will utilize LY3023414 and prexasertib to 
inhibit HR proficiency in pretreated metastatic TNBC patients. 
Patients will be treated with 150 mg LY3023414 PO BID and prexasertib 80 mg/m2 IV 
administered every 2 weeks until disease progression or unacceptable toxicity. Metastatic TNBC 
patients will undergo core needle biopsies of a metastatic lesion at study entry, and any time after 
the completion of Cycle 2 of the treatment combination, or at the physician’s discretion. If a 
research biopsy from a patient’s metastatic disease cannot be safely obtained, a skin biopsy is 
permitted. Treatment will be discontinued in patients who achieve a confirmed clinical complete 
response, and these patients will be followed to document the durability of the complete responses.  
Patients whose disease does not respond to prexasertib may be treated with standard of care breast 
cancer therapies off study, at the recommendation of the treating physician. 
Objectives:   
The primary objective of this study is to assess the objective response rate (CR+PR) associated 
with LY3023414 and prexasertib in metastatic TNBC patients. 
The secondary objectives of this protocol are: 
1. To assess the duration of response to combination treatment with LY3023414 and 
prexasertib in metTNBC pts. 
2. To assess the serial metastatic TNBC biopsy for homologous recombination deficiency 
(HRD) by evaluating inactivating mutations in HR genes on Next Generation Sequencing 
(NGS), by evaluating the overall and pattern-specific mutational load in the cancers on 
NGS, and by assessing H2AX expression by RPPA.  
3. To assess expression of phosphorylated nuclear EGFR, AKT, DNA-PK and other proteins 
involved in HR as well as activation of the PI3K, MAPK and JAK/STAT pathways in 
baseline metTNBC tissues on reverse phase protein arrays (RPPA) as possible predictors 
of clinical antitumor response to LY3023414 and prexasertib. 
Number of patients: 10 

 
Page 10 of 52 
Inclusion Criteria: 
A patient will be considered for enrollment in this study if all the following criteria are met:  
1. Patients ≥18 years of age. Patients must agree to use one highly effective (less than 1% 
failure rate) method of contraception or use a combination of two effective methods of 
contraception during treatment with study drug and for at least 12 weeks following the last 
dose of study drug. 
2. Have a diagnosis of metastatic TNBC previously treated with standard anthracycline, 
cyclophosphamide, and taxane chemotherapy, unless there was a contraindication to 
doxorubicin, in which case prior treatment with this agent is not required. NOTE: TNBC 
defined as ER-negative tumors with ≤10% tumor nuclei immunoreactivity, or “ER Low 
Positive” as defined by the updated ASCO/CAP guidelines 2020. 
3. Have not received more than 3 prior chemotherapy regimens for metastatic disease. Prior 
platinum and/or taxane therapy in the adjuvant or metastatic setting is permitted. 
4. Have locoregional (eg, breast, chest wall, regional lymphatic) or pulmonary or hepatic 
metastatic disease that is amenable to core needle biopsy. If a research biopsy from a 
patient’s metastatic disease cannot be safely obtained, a skin biopsy is permitted. If a skin 
biopsy cannot be safely obtained, patients may still be eligible, per physician discretion. 
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (See 
Appendix I) 
6. Have adequate hematologic function, defined by: 
a. Absolute neutrophil count (ANC) >1500/mm3 
b. Platelet count ≥100,000/mm3 
c. Hemoglobin ≥9 g/dL 
7. Have adequate liver function, defined by: 
a. AST and ALT ≤2.5 x the upper limit of normal (ULN) or ≤5 x ULN in presence 
of liver metastases 
b. Total bilirubin ≤1.5 x ULN 
8. Have adequate renal function, defined by: 
a. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance of ≥60 ml/min 
9. Have the ability to swallow oral medications  
10. Patients who have a history of brain metastasis are eligible for the study provided that all the 
following criteria are met: 
a. Brain metastases which have been treated 
b. Off-treatment with steroids for 2 weeks before administration of the first doses of 
LY3023414 and prexasertib 
c. No ongoing requirement for dexamethasone or anti-epileptic drugs 
d. No clinical or radiological evidence of progression of brain metastases 
11. Patient must be accessible for treatment and follow-up. 
12. All patients must be able to understand the investigational nature of the study and give 
written informed consent prior to study entry. 

 
Page 11 of 52 
Exclusion Criteria: 
A patient will be ineligible for inclusion in this study any of the following criteria are met:  
1. Have a family history of long QT Syndrome and serious cardiac conditions. 
2. Have QTcF interval of >470 msec on screening electrocardiogram (ECG) as well as on pre-
dose Cycle 1 Day 1 ECG 
3. Have insulin-dependent diabetes mellitus. Patients with a type 2 diabetes mellitus are eligible 
if adequate control of blood glucose level is obtained by oral anti-diabetics as documented by 
HbA1c <8%. Patients with type 1 diabetes mellitus are not eligible. 
4. Previous radiotherapy for metastatic disease completed <2 weeks prior to study treatment 
initiation. 
5. Women who are pregnant or lactating.  
6. Patients who have any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation such as: 
a. severe impaired lung functions as defined as spirometry and DLCO that is 50% of 
the normal predicted value and/or O2 saturation that is 88% or less at rest on room 
air 
b. liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C). 
c. viral hepatitis or HIV. 
7. Concurrent use of CYP3A4 inhibitors and inducers from 72 hours prior to initiation of study 
treatment until the end of treatment. 
8. History of any other disease, physical examination finding, or clinical laboratory finding 
giving reasonable suspicion of a disease or condition that contraindicates use of an 
investigational drug, or that might affect interpretation of the results of this study, or render 
the patient at high risk for treatment complications. 
9. Patients who have received prior PI3K or CHK therapy. 
10. Any other investigational or anti-cancer treatments while participating in this study 
11. Any other active malignancy. 
Medication 
and Doses: 
This exploratory open label pilot trial will evaluate the administration of 
LY3023414 and prexasertib in patients with metastatic TNBC. 
Metastatic TNBC patients will consent to and undergo core needle biopsies of a 
metastatic lesion for NGS, RPPA and other molecular analyses at study entry. 
Patients will then be treated with 150 mg LY3023414 PO BID and prexasertib 
80 mg/m2 IV administered every 2 weeks until disease progression or unacceptable 
toxicity. Any time after the completion of Cycle 2 of the treatment combination, or 
at the physician’s discretion, a second core needle biopsy of the same metastatic 
lesion (or different metastases if the initial metastasis has regressed) will be 
performed for RPPA and other molecular analyses. If a research biopsy from a 
patient’s metastatic disease cannot be safely obtained, a skin biopsy is permitted. 
Treatment will be discontinued in patients who achieve a confirmed clinical 
complete response, and these patients will be followed to document the durability 
of the complete responses.  

 
Page 12 of 52 
Patients whose disease does not respond to the combination of LY3023414 and 
prexasertib may be treated with standard of care breast cancer therapies off study, 
at the recommendation of the treating physician. 
Duration of 
Study: 
The duration of patient participation in the study will be a maximum of 18 months. 
Efficacy Assessments: 
CR, PR, SD, PD 
Safety Assessments: 
Toxicity  
 
 
 

 
Page 13 of 52 
PART I – CLINICAL TRIAL PROTOCOL 
1 INTRODUCTION 
1.1 
BACKGROUND ON TRIPLE NEGATIVE BREAST CANCER 
Breast cancer is the most common malignancy in women worldwide, with incidence rates as 
high as 89.7 per 100,000 women.1 Although there have been a number of important treatment 
advances in recent years, and overall mortality is declining due to earlier detection and more 
effective treatment of early stage disease, metastatic breast cancer (MBC) remains incurable and 
is the second leading cause of cancer deaths among women.2 
Triple-negative breast cancer (TNBC) is defined by the absence of ER, PgR, and HER2 receptor 
expression. By hierarchical clustering of gene expression patterns, these cancers most often 
segregate with the “basal-like” intrinsic subtype.3 Compared with other breast cancer subtypes, 
TNBC is associated with a worse prognosis, including a shorter time to recurrence in early-stage 
disease, and a shorter time between recurrence and death in the metastatic setting.4 Because 
currently available targeted therapies such as endocrine or HER2-targeted agents are ineffective 
against this breast cancer subtype, treatment options for TNBC are limited to chemotherapy at 
this time. To date, no clear molecular target has been identified and proven to have therapeutic 
value. 
1.2 
HOMOLOGOUS RECOMBINATION DEFICIENCY IN BREAST CANCER 
Seventy to 80% of breast cancers have a basal gene expression profile which is characterized by 
homologous recombination deficiency (HRD) and high proliferation.5 HRD leads to upregulation 
of the activity of the non-homologous end joining (NHEJ) error-prone pathway that repairs DNA 
double strand breaks, a process required for TNBC survival.6 A key nuclear enzyme that 
orchestrates NHEJ is DNA-Dependent Protein Kinase catalytic subunit (DNA-PKcs), a member 
of the PI3K super-family.7 
Nuclear Epidermal Growth Factor Receptor (EGFR) is activated by phospho-AKT and both 
nuclear EGFR and nuclear AKT phosphorylate and activate DNA-PK to promote NHEJ-
mediated repair of DNA double-strand breaks.8 Loss of HR proficiency, which occurs in most 
TNBCs (the basal-like TNBCs), leads to increased EGFR expression in mammary epithelial 
cells.9 However, it is not known whether activated, nuclear EGFR T564 and nuclear AKT that 
phosphorylate DNA-PK are increased in the setting of HRD in chemotherapy-resistant TNBC. 
BEZ-235 is a potent inhibitor of DNA-PKcs, as well as PI3K and TORC1/2, which inhibits 
NHEJ-mediated DNA double strand break repair, sensitizing cancers to DNA damaging agents.10  
A phase I trials of the sachet formulation of BEZ-235 demonstrated that BEZ-235 was safe with 
manageable toxicities( including mild to moderate fatigue, nausea, diarrhea, hyperglycemia, 
stomatitis and anemia) and had demonstrated antitumor activity against breast cancer.11 
However, although the mechanisms behind its activity were compelling, clinical development of 
this agent was stopped because of highly unpredictable intrapatient bioavailability that could not 
be overcome with various formulations (Novartis Oncology, personal communication, October, 
2015). 

 
Page 14 of 52 
Another mechanism which inhibits DNA repair response is the dual inhibition of mTORC1/2. In 
preclinical studies, the dual inhibition of mTORC1 and mTORC2 decreased DNA repair 
response as well as decreased the activity of AKT. This dual inhibition allowed for the partial re-
sensitization of platinum-resistant ovarian cancer cells both in vitro and in vivo to platinum 
chemotherapy, as compared to single inhibition of mTORC1.12 Blockade of the mTOR 
complexes may be a novel strategy to sensitize cancers to DNA damaging agents. 
1.3 
LY3023414 
The phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway has 
been reported as activated in >70% of human cancers and has emerged as a promising target for 
anticancer therapies. PI3K/mTOR signaling plays a central role in regulating physiological 
processes such as growth, survival, proliferation, and metabolism as well as in the development 
of malignant disease.13 Aberrations in PI3K/mTOR signaling by various mechanisms have been 
described, which lead to increased tumor proliferation, inhibition of apoptosis, and angiogenesis 
in preclinical models. In cancer patients, genes involved in signal transduction through the 
PI3K/mTOR pathway may harbor mutations more commonly than any other pathway regulating 
cell growth and survival. Such mutations are reported to occur in breast, colon, ovarian, gastric, 
prostate, mesothelioma, endometrial, brain, and lung cancers.13 
LY3023414 is an oral PI3K/mTOR inhibitor which selectively inhibits class I PI3K isoforms, 
mTOR, and DNA-PK via an ATP-competitive mechanism of action.14 In vitro, LY3023414 
demonstrated a cytostatic antiprofilerative effect, with cells accumulating in G1; no induction of 
apoptosis was observed. Strong pathway inhibition (ie, dephosphorylation of PI3K/AKT/mTOR 
pathway downstream substrates [AKT, S6K, S6RP, and 4EBP1]) was observed. Dose-responsive 
inhibition of tumor growth was observed in preclinical xenograft models when LY3023414 was 
administered as a single agent, in addition to synergistic antiproliferative effects when 
LY3023414 was combined with standard of care agents.14  
The first-in-human study of LY3023414 is a phase 1 trial that was conducted in adult patients 
with advanced solid tumors refractory to standard therapies.15 As of September 2014 (reported at 
ASCO 2015), a total of 47 patients had received LY3023414 either QD or BID. Common 
treatment-related adverse events (all grades) included nausea (38%), fatigue (31%), vomiting 
(27%), and diarrhea (17%). A durable partial response was observed in one patient with 
endometrial cancer which harbored both PIK3R1 and PTEN mutations, and 22 additional 
patients (47%) had stable disease as their best response. LY3023414 is currently being studied in 
tumor-specific expansion cohorts for mesothelioma, breast cancer, indolent Non-Hodgkin 
Lymphoma and squamous NSCLC. LY3023414 appears to be safe when administered as single 
agent up to 325 mg QD or 200 mg BID. The recommended phase 2 dose for single-agent 
LY3023414 is 200 mg PO BID, based on safety, tolerability, PK/PD, and preliminary antitumor 
activity.15 
1.4 
PREXASERTIB (FORMERLY LY2606368) 
CHK1 is a serine threonine protein kinase that is required for checkpoint-mediated cell cycle 
arrest to allow for the activation of DNA repair, once DNA damage has been detected.16,17 
Preclinical studies in triple negative breast cancer17 and head and neck cancer18 have 
demonstrated that CHK1 inhibitors can augment the cytotoxic effects of DNA-damaging 

 
Page 15 of 52 
treatments. The loss of CHK1 leads to HRD and therefore to a strong dependence on NHEJ, and 
the dual inhibition of CHK1 and NHEJ would create a synthetically lethal event.19 In addition, 
cell lines deficient in the Fanconi anemia DNA repair pathway (homologous recombination) 
have been shown to be hypersensitive to CHK1 inhibition, such that inhibiting CHK1 is 
synthetically lethal to these cells.20  
Prexasertib (previously LY2606368) is an ATP-competitive protein kinase inhibitor that showed 
selectivity to CHK1. Preclinical studies in SCLC16 demonstrated that prexasertib had notable 
single-agent activity, enhanced cisplatin cytotoxicity in platinum-resistant models, and when 
combined with the PARP inhibitor olaparib, caused tumor regression and increased survival. 
Prexasertib recently completed phase I testing, which demonstrated tolerability as well as single-
agent clinical activity in a subset of solid tumors.16 In a single arm, phase II pilot trial in BRCA 
wild type triple negative breast cancer patients, prexasertib exhibited modest single agent 
activity, warranting further evaluation as part of combination therapy.21 
A recent study of single-agent prexasertib in recurrent high-grade serous or high-grade 
endometrioid ovarian carcinoma demonstrated tolerability and clinical activity.22 Twenty-eight 
women were enrolled in the study and received at least 1 dose of prexasertib; 79% of patients 
had disease that was platinum-resistant or platinum-refractory. Of the 28 patients, 24 were 
assessable per protocol and RECIST response. Eight (33%) of 24 patients had partial responses, 
which were identified during the first tumor reassessment (in the intent-to-treat population, 
8 [29%] patients of 28 had partial response). Median progression-free survival was 7.4 months in 
the 24 assessable patients, and the most commonly reported adverse event was neutropenia in 
26 (93%) of 28 patients. This proof-of-concept, phase 2 prexasertib study in ovarian cancer with 
encouraging findings warrants further development and validation.22 
1.5 
LY3023414 AND PREXASERTIB IN COMBINATION 
Dual inhibition of the CHK1 and PI3K/mTOR signaling pathways may disrupt homologous 
recombination repair. In prexasertib-resistant TNBC PDX models, the PI3K/AKT signaling 
pathway is transcriptionally elevated. In a nonclinical model, synergistic antitumor activity was 
observed when prexasertib was combined with a PIK3K/mTOR inhibitor.23 
In a Phase 1b dose-escalation study, LY3023414 and prexasertib were given simultaneously in 
patients with advanced and/or metastatic cancer. Pharmacokinetic properties for each co-
administered agent were consistent with monotherapy PK profiles. Doses recommended for 
LY3023414 is 150 mg BID, while prexasertib recommended dose is 105 mg/m2. The most 
common adverse events were neutropenia, thrombocytopenia, anemia, nausea, and fatigue. 
These toxicities were consistent with the respective monotherapy profiles, although the incidence 
was higher. Supportive care may be required. The combination showed preliminary efficacy in 
solid tumors; in TNBC, 25% of patients had a partial response, and 37.5% had stable disease.23 
1.6 
EXCEPTIONAL RESPONDER CLINICAL HISTORY AND TUMOR MOLECULAR ALTERATIONS 
The clinical and molecular tumor characteristics of a metastatic TNBC exceptional responder 
patient to sequential treatment with BEZ-235 followed by cisplatin and nab paclitaxel provides 
the clinical rationale for conducting the proposed prospective pilot clinical trial of LY3023414 
and prexasertib.24 Briefly, after several recurrences and treatments, the patient developed a 
durable complete response (CR) after BEZ-235 therapy followed by nab paclitaxel plus cisplatin 

 
Page 16 of 52 
that has been ongoing for almost 5 years. All the patient’s serial BC specimens revealed a 
conversion from proficient homologous recombination to deficient homologous recombination, 
measured via several molecular analyses.  
Dual inhibition of CHK1 and PI3K/mTOR may disrupt homologous recombination repair, and 
the combination of LY3023414 and prexasertib has shown preliminary efficacy in a Phase 1b 
study.  
1.7 
RATIONALE 
The hypothesis of this pilot trial is that administration of LY3023414 and prexasertib will inhibit 
NHEJ in metastatic TNBC. The exceptional responder patient’s treatment history described in 
the Introduction provides the clinical rationale for the present trial which will utilize LY3023414 
and prexasertib to inhibit HR proficiency. The trial will include in depth analysis of the patients’ 
TNBC genome and phosphoproteome to evaluate HR-proficiency and deficiency, and nuclear 
proteins that drive NHEJ: at baseline and any time after completion of Cycle 2 of the treatment 
combination, or at the physician’s discretion. 
2 TRIAL OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objective of this study is to assess the objective response rate (CR+PR) associated 
with LY3023414 and prexasertib in metastatic TNBC patients. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this protocol are: 
1. To assess the duration of response to combination treatment with LY3023414 and 
prexasertib in metTNBC pts. 
2. To assess the serial metastatic TNBC biopsy for homologous recombination deficiency 
(HRD) by evaluating inactivating mutations in HR genes on Next Generation Sequencing 
(NGS), by evaluating the overall and pattern-specific mutational load in the cancers on 
NGS, and by assessing H2AX expression by RPPA.  
3. To assess expression of phosphorylated nuclear EGFR, AKT, DNA-PK and other 
proteins involved in HR as well as activation of the PI3K, MAPK and JAK/STAT 
pathways in baseline metTNBC tissues on reverse phase protein arrays (RPPA) as 
possible predictors of clinical antitumor response to LY3023414 and prexasertib. 
3 STUDY DESIGN 
This exploratory open label pilot trial will evaluate the administration of LY3023414 and 
prexasertib in patients with metastatic TNBC. 
Metastatic TNBC patients will consent to and undergo core needle biopsies of a metastatic lesion 
for NGS, RPPA, and other molecular analyses at study entry. 
Patients will then be treated with 150 mg LY3023414 PO BID and prexasertib 80 mg/m2 IV 
administered every 2 weeks until disease progression or unacceptable toxicity. Any time after the 

 
Page 17 of 52 
completion of Cycle 2 of the treatment combination, or at the physician’s discretion, a second 
core needle biopsy of the same metastatic lesion (or different metastases if the initial metastasis 
has regressed) will be performed for RPPA and other molecular analyses. If a research biopsy 
from a patient’s metastatic disease cannot be safely obtained, a skin biopsy is permitted. 
Treatment will be discontinued in patients who achieve a confirmed clinical complete response, 
and these patients will be followed to document the durability of the complete responses.  
Patients whose disease does not respond to the combination of LY302314 and prexasertib may 
be treated with standard of care breast cancer therapies off study, at the recommendation of the 
treating physician. 
4 SELECTION OF PATIENTS 
4.1 
SAMPLE SIZE 
Ten patients with metastatic TNBC will be enrolled over 12-18 months. 
4.2 
INCLUSION CRITERIA 
A patient will be eligible for inclusion in this study if he or she meets all of the following 
criteria:  
1. 
Patients ≥18 years of age. Patients must agree to use one highly effective (less than 1% 
failure rate) method of contraception or use a combination of two effective methods of 
contraception during treatment with study drug and for at least 12 weeks following the last 
dose of study drug. 
2. 
Have a diagnosis of metastatic TNBC previously treated with standard anthracycline, 
cyclophosphamide, and taxane chemotherapy, unless there was a contraindication to 
doxorubicin, in which case prior treatment with this agent is not required. NOTE: TNBC 
defined as ER-negative tumors with ≤10% tumor nuclei immunoreactivity, or “ER Low 
Positive” as defined by the updated ASCO/CAP guidelines 2020.25 
3. 
Have not received more than 3 prior chemotherapy regimens for metastatic disease. Prior 
platinum and/or taxane therapy in the adjuvant or metastatic setting is permitted. 
4. 
Have locoregional (eg, breast, chest wall, regional lymphatic) or pulmonary or hepatic 
metastatic disease that is amenable to core needle biopsy. If a research biopsy from a 
patient’s metastatic disease cannot be safely obtained, a skin biopsy is permitted. If a skin 
biopsy cannot be safely obtained, patients may still be eligible, per physician discretion. 
5. 
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (See 
Appendix I) 
6. 
Have adequate hematologic function, defined by: 
a. Absolute neutrophil count (ANC) >1500/mm3 
b. Platelet count ≥100,000/mm3 
c. Hemoglobin ≥9 g/dL 
7. 
Have adequate liver function, defined by: 
a. AST and ALT ≤2.5 x the upper limit of normal (ULN) or ≤5 x ULN in presence 
of liver metastases 

 
Page 18 of 52 
b. Total bilirubin ≤1.5 x ULN 
8. 
Have adequate renal function, defined by: 
a. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance of ≥60 ml/min 
9. 
Have the ability to swallow oral medications  
10. Patients who have a history of brain metastasis are eligible for the study provided that all 
the following criteria are met: 
a. Brain metastases which have been treated 
b. Off-treatment with steroids for 2 weeks before administration of the first doses of 
LY3023414 and prexasertib 
c. No ongoing requirement for dexamethasone or anti-epileptic drugs 
d. No clinical or radiological evidence of progression of brain metastases 
11. Patient must be accessible for treatment and follow-up. 
12. All patients must be able to understand the investigational nature of the study and give 
written informed consent prior to study entry. 
4.3 
EXCLUSION CRITERIA 
A patient will be ineligible for inclusion in this study if he or she meets any of the following 
criteria:  
1. 
Have a family history of long QT Syndrome and serious cardiac conditions. 
2. 
Have QTcF interval of >470 msec on screening electrocardiogram (ECG) as well as on pre-
dose Cycle 1 Day 1 ECG. 
3. 
Have insulin-dependent diabetes mellitus. Patients with a type 2 diabetes mellitus are 
eligible if adequate control of blood glucose level is obtained by oral anti-diabetics as 
documented by HbA1c <8%. Patients with type 1 diabetes mellitus are not eligible. 
4. 
Previous radiotherapy for metastatic disease completed <2 weeks prior to study treatment 
initiation. 
5. 
Women who are pregnant or lactating.  
6. 
Patients who have any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation such as: 
a. severe impaired lung functions as defined as spirometry and DLCO that is 50% of 
the normal predicted value and/or O2 saturation that is 88% or less at rest on room 
air 
b. liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C). 
c. viral hepatitis or HIV. 
7. 
Concurrent use of CYP3A4 inhibitors and inducers from 72 hours prior to initiation of 
study treatment until the end of treatment. 
8. 
History of any other disease, physical examination finding, or clinical laboratory finding 
giving reasonable suspicion of a disease or condition that contraindicates use of an 
investigational drug, or that might affect interpretation of the results of this study, or render 
the patient at high risk for treatment complications. 
9. 
Patients who have received prior PI3K or CHK therapy. 

 
Page 19 of 52 
10. Any other investigational or anti-cancer treatments while participating in this study 
11. Any other active malignancy 
4.4 
REASONS OFF TREATMENT 
Patients will be taken off treatment if any of the following occur (off treatment assessments 
should be completed within 30 days ± 2 days; please refer to Section 8.3):  
1. 
Disease progression on treatment 
2. 
Intolerable toxicity 
3. 
Treatment (either one or both therapies) is interrupted for more than 3 weeks for any 
reason.  
4. 
An intercurrent illness, which would in the judgment of the Investigator, affect assessments 
of clinical status to a significant degree or require discontinuation of study treatment 
5. 
Non-protocol therapy (chemotherapy, radiotherapy, hormonal therapy, immunotherapy, or 
surgery) is administered during study treatment 
6. 
Noncompliance with protocol or treatment 
7. 
Becomes pregnant 
8. 
Refuses to continue treatment (patient will continue to be followed for survival) 
9. 
Completion of treatment portion of the protocol 
10. Patients who achieve a confirmed clinical complete response 
11. Physician decision 
The date of and reason for discontinuation must be noted on the Change of Status page of the 
Case Report Form (CRF). Every effort should be made to complete the appropriate assessments. 
4.5 
REASONS OFF STUDY 
Patients will be considered off study if any of the following occur: 
1. Withdrawal of consent (patient will not be contacted and no further information will be 
collected). All data collected prior to withdrawal of consent may be used in the data 
analysis.  
2. Termination of study by Baylor IRB, Eli Lilly and Company, or Principal Investigators  
3. Lost to follow-up (3 attempts should be documented in the patient’s source document before 
the site considers the patient as LFU) 
4. Death 
The date of and reason for discontinuation must be noted on the Case Report Form (CRF). Every 
effort should be made to complete the appropriate assessments. 
If the patient is withdrawn for any reason, the end of study assessments must be completed. 
Patients who withdraw from the study treatment due to intolerable toxicity will still be followed 
for outcome and toxicity, per protocol.  
Patients must still be followed for adverse events (AEs) for 30 calendar days after their last dose 
of study drug. All new AEs occurring during this period must be reported and followed until 
resolution, or after 30 days (whichever comes first), unless, in the opinion of the investigator, 
these values are not likely to improve because of the underlying disease. In this case, the 

 
Page 20 of 52 
investigators must record his or her reasoning for this decision in the patients’ medical records 
and as a comment on the CRF. 
All patients who have CTCAE grade 3 or 4 laboratory abnormalities at the time of withdrawal 
must be followed until the laboratory values have returned to grade 1 or 2, or until 30 days after 
the date of withdrawal (whichever comes first), unless it is, in the opinion of the investigator, not 
likely that these values are to improve because of the underlying disease. In this case, the 
investigator must record his or her reasoning for making this decision in the patients’ medical 
records and as a comment on the CRF. 
5 
CONCOMITANT THERAPY 
Administration of other chemotherapy or immunotherapy, or hormonal therapy, or experimental 
medications during the study is not allowed. Patients cannot receive radiation therapy while 
receiving study therapy without previous discussion with the PI.  
Supportive care such as granulocyte colony stimulating factor (G-CSF; filgrastim; pegfilgrastim 
or other biosimilars) may be administered at the discretion of the Investigator. Replacement 
steroids are permitted. All concomitant treatments, including blood and blood products, must be 
reported on the source documentation (not necessarily in the CRF). The following concomitant 
medications must be documented on the Con Meds page of the CRF:  
• Blood and blood products 
• Antifungals 
• Prophylactic antibiotics 
• Growth factors 
• Premedications (ie, 
diphenhydramine) 
 
No herbal therapies or alternative therapies will be permitted. 
Bisphosphonates or denosumab will be allowed for treating osteoporosis or bone metastases. 
5.1 
DRUG-DRUG INTERACTIONS 
5.1.1 
LY3023414 
Drugs causing QTc interval prolongations should be avoided for all patients in the study. 
LY3023414 is a weak inhibitor of cytochrome P450 (CYP)3A4 Drugs that are either sensitive 
substrates of CYP3A4 or CYP3A4 substrates with a narrow therapeutic range should be 
administered with caution in combination with LY3023414. In addition, it is recommended to 
avoid strong inhibitors of CYP3A4 and strong and moderate inducers of CYP3A4 while 
receiving LY3023414.  
Certain fruits, fruit juices and herbal supplements (grapefruit, star fruit, Seville oranges, 
pomegranate, gingko, goldenseal) may inhibit CYP3A4 isozyme, however, the degree of that 
inhibition is unknown.26 
A sample list of drugs that have known interaction with cytochrome P450 can be found here: 
http://medicine.iupui.edu/flockhart/table.htm. 

 
Page 21 of 52 
5.1.2 
Prexasertib 
On days when prexasertib is administered, patients should avoid taking multiple (more than one) 
concomitant medications that are known or suspected to cause prolonged QTc or Torsades de 
Pointes and, if possible, alternative agents should be considered.27 
6 THERAPEUTIC AGENTS 
6.1 
LY3023414 
LY3023414 is an investigational, orally available, potent selective inhibitor of the class I PI3K 
isoforms, mTOR, and DNA-PK. LY3023414 is being evaluated as a monotherapy and in 
combination with other agents in patients with advanced and/or metastatic solid tumors. Eli Lilly 
and Company is the manufacturer of LY3023414.26 
6.1.1 
Formulation  
LY3023414 is an inhibitor of the PI3K/mTOR pathway; the chemical name is 2H-Imidazo(4,5-
c)quinolin-2-one, 8-(5-[1-hydroxy-1-methylethyl]-3-pyridinyl)-1-([2S]-2-methoxypropyl)-3-
methyl. LY3023414 is a white to light yellow solid with the molecular formulation C23H26N4O3 
and a molecular weight of 406.48. The chemical structure is below:26 
 
 
 
6.1.2 
Storage and Stability  
The drug product is packaged in bottles, which may contain desiccant, and is stable when stored 
at room temperature conditions according to the label. It is very slightly soluble in water, and 
slightly soluble in ethanol.26 
6.1.3 
Preparation and Administration  
The capsule drug product is composed of LY3023414 with no inactive ingredients, with the 
exception of the 200-mg capsules, which may also contain colloidal silicon dioxide.  
The 10-mg capsules are opaque and orangish-red in color on the body and cap. The 25-mg 
capsules are opaque and white in color on the body and cap. The 100-mg capsules are opaque 
and blue in color on the body and cap. The 200-mg capsules are opaque and orangish-red in 
color on the body and cap.  

 
Page 22 of 52 
The tablets are composed of LY3023414 and inactive ingredients such as microcrystalline 
cellulose, croscarmellose sodium, silicon dioxide, sodium stearyl fumarate, and a colorant.  
The 50-mg tablets are green, modified, capsule-shaped tablets. The 100-mg tablets are dark 
yellow, modified, capsule-shaped tablets. The 150-mg tablets are green, modified, capsule-
shaped tablets. The 200-mg tablets are light yellow, modified, capsule-shaped tablets.26 
6.1.4 
Pharmacokinetics 
Pharmacokinetic parameters of LY3023414 were evaluated in rats and dogs; data can be found in 
the prexasertib Investigator’s Brochure.26  
In summary, LY3023414 exposures are generally similar in healthy subjects and cancer patients: 
in healthy subjects, LY3023414 plasma AUC(0-∞) and Cmax are 2760 ng·hr/mL (CV 48%, n=20) 
and 777 ng/mL (CV 76%, n=20) and in cancer patients LY3023414 blood AUC(0-∞) and Cmax are 
2710 ng·hr/mL (CV 45%, n=37) and 828 ng/mL (CV 68%, n=54) following LY3023414 200 mg 
single administration. For further details, please refer to the LY3023414 Investigator’s 
Brochure.26 
6.1.5 
Adverse Effects 
For LY3023414 monotherapy (N=108), the most common (that is, occurring in ≥10% of 
patients) treatment-emergent adverse events (TEAEs) that were considered possibly related to 
LY3023414 in Study CBBA (N=96) included nausea (36.5%), fatigue (36.5%), vomiting 
(31.3%), decreased appetite (22.9%), diarrhea (20.8%), rash (13.5%), and oral mucositis 
(11.5%). Most of these TEAEs were graded as mild or moderate in severity.  
LY3023414 monotherapy has been also studied in Asian cancer patients (a Japanese cancer 
population) in Study CBBH (N=12). The most common (that is, occurring in ≥5 patients) TEAEs 
that were considered possibly related to LY3023414 in this study included stomatitis (9 patients), 
nausea (8 patients), decreased appetite (7 patients), and platelet count decreased, anemia, and 
diarrhea (each 5 patients). Most of these TEAEs were graded as mild or moderate in severity.  
The most frequently (that is, occurring in ≥4 patients) reported SAEs regardless of causality 
within the LY3023414 clinical program included dyspnea (10 patients), nausea and fatigue (each 
5 patients), and dehydration, atrial fibrillation, abdominal pain, diarrhea, deep vein thrombosis, 
and hypotension (each 4 patients).Two deaths were considered due to SAEs (1 case each of 
pneumonia and pneumonia fungal) which were not related to study treatment. For further details, 
please refer to the LY3023414 Investigator’s Brochure.26 
Pregnancy 
Animal reproduction studies have not been conducted with LY3023414. It is not known whether 
LY3023414 can affect reproductive capacity in humans. There is no clinical trial experience in 
pregnant individuals. However, based on data from an embryo–fetal developmental study, 
LY3023414 has the potential for teratogenicity and embryo/fetotoxicity and, therefore, may 
result in fetal harm when administered to a pregnant woman. LY3023414 must not be given to 
pregnant women. To minimize any potential risk, pregnant and breastfeeding women must be 
excluded from clinical trials of LY3023414. Women of childbearing potential should be advised 
to avoid becoming pregnant during therapy with LY3023414 and should be administered 
pregnancy tests prior to each cycle of treatment. Investigators should advise men to avoid 

 
Page 23 of 52 
fathering a child during therapy with LY3023414. Both males and females with reproductive 
potential must agree to use medically approved contraceptive precautions during the study and 
for at least 3 months following the last dose of the study drug. Upon documentation of 
pregnancy, the patient must be removed from the study and treatment with study drug(s) must be 
stopped immediately.26 
Nursing Mothers 
There are no available data on the effects of inhibition of PI3K and mTOR pathway on lactation. 
The potential effects of LY3023414 use during lactation are not known. Women who are 
breastfeeding should not take LY3023414.26 
Please see the Investigator’s Brochure for additional adverse events  
and complete drug information. 
 
6.2 
PREXASERTIB (LY2606368) 
Prexasertib mesylate monohydrate (hereafter, and on the cover page, referred to as prexasertib) is 
an investigational, adenosine triphosphate–competitive selective inhibitor of checkpoint kinase 1 
(CHK1). Prexasertib is being developed as a treatment for patients with advanced cancer and 
may have utility both as a single agent and in combination with other DNA-damaging agents or 
targeted agents. Eli Lilly and Company is the manufacturer of prexasertib.27 
6.2.1 
Formulation  
Prexasertib is an inhibitor of CHK1; the chemical name is 2-pyrazinecarbonitrile, 5-[[5-[2-(3-
aminopropoxy)-6-methoxyphenyl]-1H-pyrazol-3-yl]amino] monomesylate monohydrate. 
Prexasertib is a yellow to white solid with the molecular formulation C18H19N7O2·CH4O3S·H2O 
and a molecular weight of 479.51. The chemical structure is below:27 
 
 
6.2.2 
Storage and Stability  
The drug product, prexasertib for injection, is supplied for clinical trial use as a lyophilized, 
yellow to white solid in glass vials and is composed of prexasertib mesylate monohydrate and 
the inactive ingredient sulfobutylether-β-cyclodextrin (Captisol). The drug product is available as 
either a 40 mg or 20 mg strength vial of the base compound prexasertib. The 40-mg strength vial 

 
Page 24 of 52 
contains a 3% excess and the 20 mg strength contains a 5% excess to facilitate the withdrawal of 
the label amount for application with an appropriate device, such as an infusion set. 
The drug product is stable when stored at room temperature. The reconstituted formulation is 
stable for at least 24 hours at room temperature; however, because the reconstituted drug product 
does not contain a preservative, the unused solution must be discarded after 12 hours.27 
6.2.3 
Preparation and Administration  
Reconstituting the 40-mg or 20 mg vial contents with 19 mL or 10 mL of water, respectively, 
yields a clear yellow solution with a concentration of 2 mg/mL of prexasertib, pH 4 to 6, and an 
osmotic pressure ratio of 344 mOsm. 
The reconstituted solution may be diluted with dextrose 5% injection before administration. 
Prexasertib is incompatible with solutions containing saline or lactated Ringer’s and must not be 
mixed or administered simultaneously with other drugs through the same infusion line. A 
separate document detailing specific instructions regarding filtering and drug administration will 
be provided by Eli Lilly and Company for the clinical study.  
Prexasertib should be handled according to standard procedures and precautions consistent with 
a cytotoxic anticancer drug.27 
6.2.4 
Pharmacokinetics 
The plasma toxicokinetics of prexasertib were evaluated in rats and dogs; data can be found in 
the prexasertib Investigator’s Brochure.27 
Pharmacokinetic data are available for prexasertib from a total of 146 patients from Parts A, B, 
and C from Study JTJA, 153 patients across the dose range of 20 to 105 mg/m2 from Parts A, B, 
C, D, and E of Study JTJF, 26 patients from JTJI, 9 patients from JTJL, 116 patients from JTJH, 
100 patients from Study JTJN, 12 patients in Study JTJK, and 6 patients from Study JTJG. For 
further details, please refer to the prexasertib Investigator’s Brochure.27 
6.2.5 
Adverse Effects 
The safety profile of prexasertib is consistent with toxicities commonly observed with standard-
of-care cytotoxic agents used to treat cancer (for example, neutropenia, thrombocytopenia, and 
anemia). Complications from these toxicities such as febrile neutropenia, infections, and 
clinically significant bleeding events can be mitigated by supportive care approaches such as 
administration of granulocyte-colony-stimulating factor (G-CSF) and transfusions. 
Nonhematologic toxicities deemed related to prexasertib treatment occur at a much lower 
frequency and severity, with fatigue, nausea, diarrhea, decreased appetite, and vomiting being 
the mostly commonly observed events. Infusion-related reactions have been observed in patients 
who received prexasertib. For further details, please refer to the prexasertib Investigator’s 
Brochure.27 
Prexasertib and QTc 
In nonclinical toxicology studies in dogs, dose-progressive prolongation of QRS duration and 
QTc interval was observed. Across Studies JTJA and JTJK, the largest mean QTcF increases 
from baseline (<15 ms) occurred at the end of the prexasertib infusion. On average, increases in 

 
Page 25 of 52 
QTcF values from baseline were <10 ms 1 to 2 hours following the end of infusion and returned 
to predose values within approximately 24 hours. Taken together, since prexasertib is given IV 
and concentrations decline quickly after the end of infusion, the observed QTcF changes would 
be transient in nature and are not considered an important risk to patients at this time. 
In Study JTJA, the maximal QTcF increase from baseline was 39 ms and no event of QTcF 
prolongation was associated with an SAE. Across the program, Torsades de Pointes or serious 
arrhythmias have not been reported. 
Electrocardiograms should be evaluated for changes in QT/QTc interval. Patients with additional 
risk factors for Torsades de Pointes, including heart failure, a prolonged QTc interval >470 ms 
on screening ECG, or a family history of long QT syndrome, should be excluded from clinical 
trials. On days when prexasertib is administered, patients should avoid taking multiple (more 
than 1) concomitant medications that are known or suspected to cause prolonged QTc or 
Torsades de Pointes and, if possible, alternative agents should be considered. In addition, at the 
start of the study and on days when prexasertib is administered, care should be taken to ensure 
that there are no abnormal levels of electrolytes that could increase the risk for ECG changes.27 
Pregnancy 
The potential treatment effects of prexasertib use during pregnancy and lactation are not known. 
Nonclinical studies of prexasertib on pregnancy and fetal development have not been performed. 
To minimize any potential risks, men and women with reproductive potential should use 
medically approved contraceptive precautions during treatment and for 3 months after the last 
dose of prexasertib.27 
Nursing Mothers 
The potential treatment effects of prexasertib use during lactation are not known. Women who 
are breastfeeding should not receive prexasertib.27 
Please see the Investigator’s Brochure for additional adverse events and complete drug 
information. 
7 
INVESTIGATIONAL PLAN 
7.1 
REGISTRATION PROCEDURES 
Written documentation of full, noncontingent IRB approval must be on file before a patient can 
be registered. The registration process begins when the Coordinator has obtained a signed 
informed consent.  
A patient identification number is directly assigned once the patient is found eligible. Patient ID, 
consent date, status of patient (eg, active or screen failure), relevant comments, and date of 
patient discontinuation are to be recorded on the Patient Log by the Coordinator. The Patient Log 
will be kept in a binder for review for any reason (ie, monitoring/audit). Once a patient ID is 
assigned, this will constitute the registration confirmation. Treatment must begin within 
20 working days (not counting the day of dosing) after the patient’s registration on the 
study.  

 
Page 26 of 52 
The PI may be allowed the opportunity to review and grant exceptions for minor deviations in 
eligibility, in order to maximize patient accrual without jeopardizing patient safety or scientific 
integrity of these studies. Examples might include minor deviations of baseline labs, timing of 
prior treatment or tests, etc. It is recognized that these questions arise frequently. The procedure 
to be followed is for the Investigator or his/her representative (eg, research nurse) to e-mail the 
request to the PI for an exception. The PI would then make a determination, which is binding. In 
no instance should this exception constitute a safety issue for the patient or a significant 
deviation from the scientific purpose of the study.  
7.2 
STUDY TREATMENT ADMINISTRATION 
Patients will receive prexasertib as an approximately 60-minute infusion on Day 1 and Day 15 of 
a 28-day cycle. Oral LY3023414 will be administered twice a day (BID) on Days 1 to 28 of a 28-
day cycle. On prexasertib dosing days, the administration of LY3023414 will follow 
immediately after the end of the prexasertib infusion (within 5 minutes) on Day 1 of each cycle. 
Patients should take the morning and evening doses of LY3023414 approximately 12 hours apart 
(preferably within a 10- to 14-hour range). Please refer to Sections 7.2.2.1 and 7.2.2.2 for further 
details. 
7.2.1 
Premedications 
LY3023414 
There is no required premedication for the administration of LY3023414.26 
Prexasertib 
Premedication with diphenhydramine hydrochloride 25-50 mg IV and/or other equivalent 
premedication may be administered at the physician’s discretion.27 
7.2.2 
Treatment Plan 
1. Once patients sign informed consent, they will be evaluated with a complete history, physical 
examination as well as initial studies as described in Section 8.1.  
2. Metastatic TNBC patients will undergo core needle biopsies of a metastatic lesion for NGS, 
RPPA, and other molecular analyses at study entry. 
3. Patients will then be treated with 150 mg LY3023414 PO BID and prexasertib 80 mg/m2 IV 
administered every 2 weeks until disease progression or unacceptable toxicity. 
4. Any time after the completion of Cycle 2 of the treatment combination, or at the physician’s 
discretion, a second core needle biopsy of the same metastatic lesion (or different metastases 
if the initial metastasis has regressed) disease will be performed for RPPA and other 
molecular analyses. If a research biopsy from a patient’s metastatic disease cannot be safely 
obtained, a skin biopsy is permitted. 
5. Treatment will be discontinued in patients who achieve a confirmed clinical complete 
response, and these patients will be followed to document the durability of the complete 
responses. 
6. Patients whose disease does not respond to the combination of LY302314 and prexasertib 
may be treated with standard of care breast cancer therapies off study, at the 

 
Page 27 of 52 
recommendation of the treating physician. 
The treatment schema is shown in Table 1.   
 
Table 1. 
Treatment schema 
Agent 
Dose 
Frequency of 
administration 
Route of 
administration 
LY3023414a 
150 mg 
BID 
PO 
Prexasertib 
80 mg/m2 
Days 1 and 15 
of 28 days 
IV 
a Doses are administered orally BID approximately 12 hours apart on Days 1 through 28 of each 28-day 
cycle. 
 
7.2.2.1 
LY3023414 
Doses are administered orally BID approximately 12 hours apart (preferably within a 10- to 14-
hour range) on Days 1 through 28 of each 28-day cycle. LY3023414 capsules should be taken at 
approximately the same time on each dosing day. LY3023414 may be administered with or 
without food. Patients may experience improved GI tolerability of LY3023414 when it is taken 
with or just after a meal. Patients should also be monitored in order to detect and treat 
mucositis/stomatitis early before it becomes severe. 
On prexasertib dosing days, patients will receive prexasertib first (see Section 7.2.2.2). The 
administration of LY3023414 will follow immediately at the end of the prexasertib infusion 
(within 5 minutes of infusion end). 
If the patient misses a dose of LY3023414, the patient should take the dose as soon as possible, 
but not less than 6 hours before the next dose is due for BID dosing. If the next dose is due in 
less than 6 hours, the patient should skip the missed dose and take the next dose as scheduled. 
LY3023414 should be stored within the temperature range stated on the label. Patients should be 
instructed to store the drug product at home in the provided container and to keep out of the 
reach of children. The drug product should not be crushed or dissolved. Capsules should not be 
opened.26 
7.2.2.2 
Prexasertib 
Prexasertib is administered as an IV infusion over 1 hour using a central or free-flowing 
peripheral IV line with an appropriate filter. Prexasertib should not come in contact with normal 
saline; the infusion line should be flushed with dextrose 5% injection before and after prexasertib 
administration. 
On prexasertib dosing days, patients will receive prexasertib first. The administration of 
LY3023414 will follow immediately at the end of the prexasertib infusion (within 5 minutes of 
infusion end). 
There is a low incidence of infusion reactions: In the event of a suspected infusion-related 
reaction, institutional guidelines for managing infusion reactions should be followed. For 
subsequent infusions, premedication with diphenhydramine and/or other premedication (see 

 
Page 28 of 52 
Section 7.2.1) may be administered at the physician’s discretion. The infusion rate may also be 
decreased by up to 50% after recovery from the infusion-related reaction. The patient should be 
monitored for signs and symptoms indicative of an infusion-related reaction. 
The actual doses of prexasertib to be administered are determined by calculating the BSA for 
each patient at the beginning of each cycle.27 
7.2.3 
Treatment Delay 
Patients will be allowed to stay on either of the therapies if they need to delay one for toxicity. If 
a treatment day variation is needed for reasons other than toxicity, an attempt should be made to 
keep the variation within the following parameters: 4 calendar days for 28-day cycles. Any 
delay within this window is NOT a deviation. Note: This delay window does not apply to 
Cycle 1.  
1. Treatment (either one or both therapies) may be delayed no more than 3 weeks for any 
reason.  
2. Patients who are off study treatment for more than 3 weeks for any reason will be considered 
off treatment. 
3. If patients miss doses for less than 2 weeks due to toxicities, the doses will not be made up.  
4. If patients miss doses for less than 2 weeks due to reasons other than toxicity (car broke 
down, missed the bus, etc), the doses will be made up. 
7.2.4 
Dose Modification for Toxicity 
Dose reductions are to be made according to the system showing the greatest degree of toxicity. 
Toxicities will be graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03 as linked in Appendix I. At each clinic visit, treatment with 
LY3023414 or with prexasertib will continue if:  
• ANC ≥1000 (if pegfilgrastim is being used) or of ≥1200/mm3 (if no pegfilgrastim 
is being used) 
• Platelets ≥75,000/mm3 
• Resolution of nonhematologic toxicities to ≤Grade 1 or baseline 
7.2.4.1 
LY3023414 Dose Modifications 
Dose reductions will be at the physician’s discretion. Two dose reductions are permitted for 
LY3023414. Dose reductions beyond Level -2 would result in discontinuation of treatment. Re-
escalation to the previous dose is acceptable in the absence of continuing toxicity, provided that 
this dose is not greater than current dose being tested. If subsequent dose reduction is required 
after re-escalation, the patient must be maintained at the reduced dose level for all remaining 
cycles. 
The dose reduction levels for LY3023414 are shown in Table 2. 
 
 

 
Page 29 of 52 
Table 2. 
LY3023414 Dose Reduction Levels  
Level 
LY3023414 
Starting Dose 
(Level 0) 
150 mg Q12H 
Level -1 
100 mg Q12H 
Level -2 
100 mg Q24H 
Abbreviations: Q12H = every 12 hours; Q24H = every 24 hours 
Nonhematologic Toxicity: 
For nonhematologic toxicities that are  grade 2, manage symptomatically if possible, and 
resume without dose reduction.  
For nonhematologic Grade 3 or 4 toxicities (excluding nausea and alopecia), the treatment 
should be withheld until the patient recovers completely or to Grade 1 toxicity. This reduction 
should be permanent. If the treatment was withheld for more than 3 weeks, the patient will be 
taken off treatment. 
Hematologic Toxicity: 
Treatment decisions and dose reductions should be made based on ANC and platelet counts on 
the day of treatment administration. A reduction due to low hematologic values on the day of 
treatment is not permanent and is made on each treatment visit. Dose modifications must be 
recorded on the CRF. 
• Patients must have ANC of ≥1000/mm3 on Day 1 of each cycle (if pegfilgrastim is 
being used) or of ≥1200/mm3 on Day 1 (if no pegfilgrastim is being used) to receive 
scheduled treatment. Treatment may be delayed to allow sufficient time for recovery. 
• Patients must have a platelet count of ≥75,000/mm3 on Day 1 of each cycle to receive 
scheduled treatment. LY3023414 should be delayed until platelet counts recover to 
≥75,000/mm3 and then treated with either full dose or reduced dose at the physician’s 
discretion. Treatment may be delayed to allow sufficient time for recovery. 
Use of hematopoietic growth factors to ameliorate hematologic toxicity is at the discretion of the 
physician investigator and guidance from Eli Lilly. 
7.2.4.2 
Prexasertib Dose Modifications 
Dose modifications will be at the physician’s discretion. One dose reduction and one dose 
escalation are permitted for prexasertib. Dose reductions beyond Level -1 would result in 
discontinuation of treatment.  
Patients who tolerate Cycles 1 and 2 without Grade 4 hematologic or Grade 3-4 nonhematologic 
toxicity may have the prexasertib dose increased on Cycle 3 to Level +1 (105mg/m2) at the 
physician’s discretion. 
 
 
 
 

 
Page 30 of 52 
The dose modification levels for prexasertib are shown in Table 3. 
Table 3. 
Prexasertib Dose Modification Levels  
Level 
Prexasertib 
Level +1a 
105 mg/m2 
Starting Level 0 
80 mg/m2 
Level -1 
60 mg/m2 
Abbreviations: Q12H = every 12 hours; Q24H = every 24 hours 
aPatients who tolerate Cycles 1 and 2 without Grade 4 hematologic or 
Grade 3-4 nonhematologic toxicity may have the prexasertib dose 
increased on Cycle 3 to Level +1 at the physician’s discretion. 
 
Additional dose adjustments and delays are below in Table 4: 
Table 4. 
Additional dose adjustment guidance for prexasertib 
Toxicity 
CTCAE Grade 
Action 
Dose Adjustments and 
Considerations 
Neutropenia 
Grade 3 or 4 
Delay treatment until 
≤Grade 2 (≥1000/mm3 if 
pegfilgrastim is being 
used, or ≥1200/mm3 if no 
pegfilgrastim is used) 
Investigator discretion; 
consider prophylactic G-
CSF 
Thrombocytopenia 
Grade 3 or 4 
Delay treatment until 
≤Grade 1 (≥75/mm3) 
Investigator discretion 
Anemia 
Grade 3 or 4 
Consider RBC transfusion 
or EPO (if consistent with 
institutional guidelines). 
Treatment may proceed or 
be delayed at the 
discretion of the 
investigator. 
Investigator discretion 
Febrile neutropenia 
(without prophylactic G-
CSF) 
Any grade 
Delay treatment until 
afebrile and neutrophils 
≤Grade 2 (≥1200/mm3) 
Investigator discretion; 
consider prophylactic G-
CSF 
Febrile neutropenia (with 
prophylactic G-CSF) 
Any grade 
Delay treatment until 
afebrile and neutrophils 
≤Grade 2 (≥1000/mm3) 
Reduce to next lower 
dose level unless there is 
documented agreement 
between investigator and 
CRP/CRS 
Allergic/hypersensitivity 
reactiona 
Grade 1 or 2 
Administer treatment per 
institutional guidelines for 
allergic/hypersensitivity 
reactions. Monitor closely 
for any worsening 
symptoms. A reduced rate 
can be used for 
subsequent infusions. 
Investigator discretion 
 
≥Grade 3 
Stop infusion immediately and disconnect infusion 
tubing from the patient. Administer treatment per 
institutional guidelines. Patient must not receive any 
further treatment with prexasertib. 

 
Page 31 of 52 
Other nonhematologic 
toxicityb 
Grade 2 
Delay treatment until 
≤Grade 1 or baselinec 
Investigator discretion 
 
Grade 3 or 4 
Delay treatment until 
≤Grade 1 or baselinec 
Reduce to next lower 
dose level 
Abbreviations: CRP = clinical research physician; CRS = clinical research scientist; CTCAE = common terminology criteria 
for adverse events version 4.0; EPO = erythropoietin; G-CSF = granulocyte colony stimulating factor; RBC = red blood cells. 
a Please refer to the IB for the most recent guidance on allergic/hypersensitivity reactions. 
b Except alopecia, fatigue, or toxicities that can be controlled with adequate treatment such as nausea, vomiting, diarrhea, or 
asymptomatic electrolyte disturbances. 
c Baseline is considered prior to dosing on Cycle 1 Day 1. 
Nonhematologic Toxicity: 
For nonhematologic toxicities that are  Grade 2, manage symptomatically if possible, and 
resume without dose reduction.  
For nonhematologic Grade 3 or 4 toxicities (excluding nausea and alopecia), the treatment 
should be withheld until the patient recovers completely or to Grade 1 toxicity. This reduction 
should be permanent. If the treatment was withheld for more than 3 weeks, the patient will be 
taken off treatment. 
Hematologic Toxicity: 
Treatment decisions and dose modifications should be made based on ANC and platelet counts 
on the day of treatment administration (see Table 4 for guidance). A reduction due to low 
hematologic values on the day of treatment is not permanent and is made on each treatment visit. 
Dose modifications must be recorded on the CRF. 
• Patients must have ANC of ≥1000/mm3 on Day 1 of each cycle (if pegfilgrastim is 
being used) or of ≥1200/mm3 on Day 1 (if no pegfilgrastim is being used) to receive 
scheduled treatment. Treatment may be delayed to allow sufficient time for recovery. 
• Patients must have a platelet count of ≥75,000/mm3 on Day 1 of each cycle to receive 
scheduled treatment. Prexasertib should be delayed until platelet counts recover to 
≥75,000/mm3 and then treated with either full dose or reduced dose at the physician’s 
discretion. Treatment may be delayed to allow sufficient time for recovery. 
Use of hematopoietic growth factors to ameliorate hematologic toxicity is at the discretion of the 
physician investigator and guidance from Eli Lilly. 
7.3 
TOXICITY 
Toxicities will be graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 as linked in Appendix I. This document can also be downloaded 
from the Cancer Therapy Evaluation Program (CTEP) home page <http://ctep.cancer.gov>. 
Events must be documented on the AE page of the CRF. 
8 SCHEDULE OF ASSESSMENTS 
The schedule of assessments for the trial is shown in Appendix II. If a required observation or 
procedure is missed, documentation is required in the source records, on the Protocol Deviation 
Form, and on the CRF, to explain the reason for this protocol deviation. 

 
Page 32 of 52 
For scheduling purposes, Day 1 is the first day of treatment administration. Return appointments 
must always be scheduled from Day 1 of the study. It is imperative that all visits occur within the 
specified windows. 
8.1 
PRESTUDY ASSESSMENTS  
Note: Assessments that are part of the standard of care and obtained within 3-4 weeks of the 
prestudy assessment visit are acceptable as part of the screening tests. Results of such tests will 
be acceptable even if obtained prior to the execution of the Inform Consent Form. 
Prior to entry into the study, the following assessments will be performed to determine if patient 
is eligible to continue in the study as per Sections 4.2 and 4.3 describing the inclusion and 
exclusion criteria for the study. 
1. A signed Patient Informed Consent Form must be obtained. 
2. A signed Patient Authorization Form (HIPAA) must be obtained. 
3. It has been confirmed that the patient meets all inclusion criteria and none of the exclusion 
criteria. 
4. A complete medical history must be obtained within 4 weeks prior to registration. 
5. A complete physical examination (including vital signs, height, and body weight) must be 
obtained within 4 weeks prior to registration. 
6. Assessment of PS on the ECOG scale (Appendix III) must be obtained within 4 weeks 
prior to registration. 
7. Assessment of concomitant medications must be obtained within 4 weeks prior to 
registration. 
8. A complete blood count (CBC) with differential and platelet count within 4 weeks prior to 
registration. 
9. Complete metabolic profile (CMP) including: serum chemistries (creatinine, glucose, total 
protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, 
alkaline phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) 
and electrolytes (total calcium, chloride, potassium, sodium), must be performed within 
4 weeks prior to registration.  
10. Assessment of magnesium (Mg) and phosphorus (P) within 4 weeks prior to registration. 
11. HbA1c must be performed within 4 weeks prior to registration. 
12. Fasting serum glucose must be performed within 4 weeks prior to registration. 
13. Females of childbearing potential must have a serum pregnancy test performed within 
7 calendar days prior to registration. Women of child-bearing potential participating must 
agree to use one highly effective (less than 1% failure rate) method of contraception or use a 
combination of two effective methods of contraception during treatment with study drug and 
for at least 12 weeks following the last dose of study drug. 
14. ECG must be performed within 4 weeks prior to registration. 
15. A clinical assessment of the patient’s disease (ie, by physical examination) must be 
performed within 4 weeks prior to registration.  

 
Page 33 of 52 
16. Radiological assessment of tumors (ie, chest and abdomen CT scan) must be performed 
within 8 weeks prior to registration. The methods used for prestudy assessments should 
be used throughout the study. If possible, the same equipment should be used each time. 
17. Assessments of other lesions by physical exam must be performed within 4 weeks prior to 
registration. 
18. If safely accessible, research biopsies of the patient’s metastatic locoregional or pulmonary 
or hepatic disease must be obtained prior to the first day of treatment. If a research biopsy 
from a patient’s metastatic disease cannot be safely obtained, a skin biopsy is permitted. If a 
skin biopsy cannot be safely obtained, patients may still be eligible, per physician discretion. 
19. Whole blood collection (40 mL) for germline exome sequencing studies. 
20. Distribution of LY3023414 dosing and treatment adverse events patient diaries (see 
Appendix V). 
8.2 
ASSESSMENTS DURING TREATMENT 
The following assessments will be performed during therapy on Day 1 prior to the start of each 
cycle, unless otherwise specified. A Cycle is defined as 28 days (prexasertib dosing on Day 1 
and 15).  
There is a window (up to 4 calendar days prior to the scheduled time point) for assessments 
during the study. Any delay within this window is NOT a deviation. Assessments that are to be 
done on days when study drug is administered must be done prior to dosing as these 
assessments (CBC, CMP, assessment of response, etc) may determine whether or not drug is 
administered, or if a dose reduction is necessary, unless otherwise noted.  
Note for Cycle 1 only: the prestudy assessments that correspond to assessments below may be 
used as Cycle 1 assessments as long as they are completed within the 72 hours prior to the 
patient receiving their first dose of study drug. If more than 72 hours have elapsed since the 
prestudy assessment, the assessment must be repeated for Cycle 1. 
1. A brief medical history, to capture events that have occurred since the last cycle. Events that 
were not captured in the baseline complete medical history should be recorded on the AE 
page of the CRF. 
2. A brief physical examination, including vital signs and body weight 
3. ECOG PS (Appendix III) 
4. Assessment of concomitant medications 
5. A CBC with differential and platelet count on Day 1 and Day 15 of every cycle 
6. A CMP Day 1 and Day 15 of each cycle 
7. Assessment of magnesium (Mg) and phosphorus (P) Day 1 and Day 15 of each cycle 
8. HbA1c must be obtained Day 1 and Day 15 of each cycle 
9. Fasting serum glucose must be obtained Day 1 and Day 15 of each cycle  
10. A pre-dose ECG (within 10 minutes of beginning prexasertib infusion) must be obtained on 
Cycle 1 and Cycle 2. Additional ECG may be obtained if clinically indicated. 
11. A post-dose ECG (within 10 minutes of ending prexasertib infusion) must be obtained on 
Cycle 1 and Cycle 2. Additional ECG may be obtained if clinically indicated. NOTE: it is 

 
Page 34 of 52 
preferred to complete the post-dose ECG upon completion of the prexasertib infusion, but 
prior to LY3023414 dosing. 
12. Tumor response by clinical assessment of the patient’s disease (ie, by physical examination)  
13. Radiological assessment of tumors (ie, chest and abdomen CT scan) every 8 weeks or as 
clinically indicated. The methods used for prestudy assessments should be used throughout 
the study. If possible, the same equipment should be used each time. 
14. Assessments of other sites of disease must be performed only to confirm a CR.  
15. Toxicity 
16. If safely accessible, research biopsies of the same metastatic lesion (or different metastases if 
the initial metastasis has regressed) may be obtained any time after the completion of 
Cycle 2 of the treatment combination, or at the physician’s discretion. If a research 
biopsy from a patient’s metastatic disease cannot be safely obtained, a skin biopsy is 
permitted. 
17. Whole blood collection (40 mL) for germline exome sequencing studies any time after the 
completion of Cycle 2 of the treatment combination, or at the physician’s discretion. 
18. Patient diary assessment of LY3023414 dosing and treatment adverse events  
8.3 
OFF TREATMENT/END OF TREATMENT ASSESSMENTS 
This is a single assessment that will be performed within 30 days ± 2 days when a patient 
finishes treatment or goes off treatment because of PD, toxicity that places patients off treatment, 
if patients achieve a confirmed clinical complete response, or in cases of physician decision or 
where patient withdraws consent. Patients who withdraw consent may not want any further 
assessments; however, they should be encouraged to have these final assessments done. 
NOTE: End of treatment, or off treatment, is NOT considered off study or withdrawn from the 
study. 
The following evaluations will be performed at this visit:  
1. A brief medical history should be done to capture events that have occurred since the last 
cycle. Events that were not captured in the baseline complete medical history should be 
recorded on the AE page of the CRF. 
2. A brief physical examination, including vital signs and body weight. 
3. A CBC with differential and platelet count. 
4. A CMP   
5. A serum pregnancy test 
6. A tumor clinical assessment of the patient’s disease (ie, by physical examination) 
7. A toxicity assessment 
8. Collection of any outstanding patient diaries 
8.4 
FOLLOW UP ASSESSMENTS 
The duration of patient participation in the study will be a maximum of 18 months, which is 
counted from the start of treatment, provided progressive disease has not occurred. Follow-up 
visits will be performed every 3 months for 1 year from the date of last treatment dose. Only 
research data will be collected during this time. 

 
Page 35 of 52 
Note: Patients who die or withdraw consent are considered off study and no further information 
will be collected. 
1. Additional therapy  
2. Date and site of relapse or progression  
3. Survival status  
4. Toxicities will be recorded for the first 30 days following the last study treatment. 
5. Clinical and radiological tumor assessment as per standard of care 
8.5 
BLOOD SAMPLES FOR EXOME SEQUENCING 
Whole blood collection (40 mL) for exome sequencing studies will be obtained at baseline and 
any time after the completion of Cycle 2 of the treatment combination, or at the physician’s 
discretion  
No information that identifies the patient will be given to any of the laboratories that will analyze 
blood samples. Any material analyzed will be supplied with code number identifiers only, 
without the patient’s name or other identifying information. Access to the database which 
contains patient identifiers is limited to study investigators and project managers only and is 
safeguarded by a password protection system. Passwords are not shared. If research findings are 
published from this study, the research patient will not be identified by name. 
8.6 
BIOPSIES 
Research biopsies will be obtained at the following time points (See Appendix IV for tissue 
collection and handling): 
• A minimum of four 14-gauge needle biopsy cores (or the largest core biopsy deemed 
safe) may be collected at baseline, prior to the initiation of treatment. 
• A minimum of four 14-gauge needle biopsy cores (or the largest core biopsy deemed 
safe) may be collected any time after the completion of Cycle 2 of the treatment 
combination, or at the physician’s discretion.  
Second research biopsies may be obtained from a different metastasis if the initial metastasis has 
regressed. Tissue biopsies of a patient’s metastatic locoregional or pulmonary or hepatic disease 
will be analyzed by next generation sequencing (NGS) for mutations in DNA repair and PI3K 
pathways, as well as others. Remaining tissue will be frozen and/or formalin-fixed paraffin 
embedded (FFPE) for biomarker development. 
If a research biopsy from a patient’s metastatic disease cannot be safely obtained, a skin biopsy 
is permitted. 
9 SAFETY EVALUATIONS 
9.1 
ADVERSE EVENTS 
All Grade 3 and 4 adverse events (AEs), Grades 1 and 2 alopecia, and all grades of neutropenia 
will be recorded in the CRF throughout the trial. In addition, all treatment-related Grade 1 and 2 
laboratory abnormalities, which are deemed “clinically significant” by the Treating Physician 
will be documented in the CRF.  

 
Page 36 of 52 
Adverse events (AEs) will be recorded throughout the trial. Toxicities and AEs will be graded 
using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 as linked in 
Appendix I. The events, and the relationship of each event to treatment, will be assessed by the 
Treating Physician and recorded on the CRF. Additional information about each event, such as 
treatment required, eventual outcome, and whether or not therapy had to be interrupted or 
dosages reduced, will also be recorded on the CRF. Adverse events will be recorded for up to 
30 days following the last study treatment. 
Definitions and additional reporting instructions are provided in Part II of this protocol. 
9.2 
LABORATORY DATA 
For the treatment of the patient, laboratory data will be obtained according to the schedule of 
assessments. Only the laboratory data requested on the CRF need to be recorded on the 
appropriate laboratory CRF page. In addition, abnormal results that are associated with an AE 
will be documented on the Adverse Event page of the CRF if the laboratory abnormality fits the 
definition of an AE or can potentially result in an AE. 
10 EFFICACY ASSESSMENTS (SOLID TUMOR) 
All efficacy assessments will be investigator assessments of response, time to response, and 
duration of response. Investigator will determine objective response rate, complete response 
(CR), partial response (PR), stable disease (SD), or progression of disease (PD). 
 
 

 
Page 37 of 52 
11 STATISTICAL CONSIDERATIONS 
11.1 
POPULATIONS FOR ANALYSIS 
11.1.1 
Analysis Populations 
Intent-To-Treat (ITT) Population: Includes all patients registered on the study (eligible and 
ineligible). This population will be included in overall patient listings, in summary tables of 
patient demographics and baseline disease characteristics, and also in the list of treatment 
discontinuations after enrollment. 
Evaluable Population: Includes all eligible patients who meet the protocol-specified efficacy 
analyses requirements and who have received at least 1 dose of study drugs. This population will 
comprise those patients who will be assessed for pathologic response. Early discontinuation of 
treatment (in Cycles 1-2), secondary to toxicity, will be considered a treatment failure. If death 
occurs before the completion of 1 cycle, the patient will be reported as evaluable, early death, but 
deemed not evaluable for response. 
Safety Population: Includes all patients (eligible and ineligible) who receive at least 1 dose of 
study drugs. This safety population will also be used for the summaries and analysis of all safety 
parameters (drug exposure, tables of adverse events information, including serious adverse 
events, etc.). Adverse events that are unrelated to treatment and that occur >30 days after the 
administration of treatment will not be reported or analyzed. 
11.1.2 
Patient Characteristics 
Patient characteristics including demographics and pretreatment characteristics, breast mass and 
axillary lymph node size, staging evaluation at baseline, medical history, and family history will 
be summarized. Descriptive statistics including sample size, mean, standard deviation, median, 
and minimum and maximum values will be presented for continuous variables. Frequency 
distributions will be presented for categorical variables. 
11.1.3 
Patient Disposition 
Patient disposition including the number of patients enrolled, completed, and discontinued from 
the study will be summarized overall and by study site. The reasons for discontinuation will also 
be summarized, and patients who discontinued will be listed. 
11.2 
HYPOTHESIS AND ENDPOINTS 
The hypothesis of this proof of concept pilot trial is that administration of LY3023414 and 
prexasertib will inhibit NHEJ in metastatic TNBC. 
This is an exploratory and descriptive clinical trial in which the primary objective is to assess the 
objective response rate associated with LY3023414 and prexasertib in metastatic triple negative 
breast cancer patients. 
The secondary objectives of this trial are to assess the duration of response; assess the metastatic 
TNBC tissues for homologous recombination proficiency and deficiency; and assess expression 
of phosphorylated proteins involved in homologous recombination. 

 
Page 38 of 52 
11.3 
SAMPLE SIZE 
Ten patients will be enrolled over 12-18 months. 
11.4 
STATISTICAL METHODS 
Ten patients with metTNBC will be enrolled on study and will be treated with LY3023414 and 
prexasertib. If 0-1 of 10 patients has an objective response to treatment, enrollment will be 
stopped. If at least 2 of 10 patients has an objective response with treatment, an additional 
10 patients could be enrolled on study, following discussion and agreement with Lilly. 
Expanding the number of patients to 20 would require a protocol amendment. With a sample size 
of 20 patients, there is an 60% chance of observing 4 or more responses if the true response rate 
is at least 20%. The complete response rate and duration of response will also be assessed to 
determine if the combination of LY3023414 and prexasertib will produce exceptional responses 
of at least 12 months in duration. 
A 30% or greater rate of durable (at least 12 months) complete or partial responses would be of 
high clinical interest and would justify further development of this therapeutic strategy.    

 
Page 39 of 52 
PART II – PROCEDURES 
12 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
All AEs, regardless of severity, will be followed up by the Investigator until resolution is 
satisfactory. All AEs will be recorded for up to 30 days following the last study treatment. 
12.1 
DEFINITIONS 
12.1.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject, administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
12.1.2 
Serious Adverse Event 
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any 
dose: 
• Results in death,  
(NOTE: Any death from any cause while a patient is receiving treatment on this protocol, 
or  30 days following the last dose of protocol treatment must be reported.) 
• Is life-threatening, 
(NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.) 
• Requires inpatient hospitalization or prolongation of existing hospitalization,  
(NOTE: Hospitalization is considered an overnight stay, therefore visits to hospital, without 
admission, are not considered serious unless they meet another criterion, (eg, medically 
significant). Planned surgery, or planned admission for study drug, is not considered an SAE 
unless, the hospitalization is prolonged or if another criterion is met.) 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Additionally, important medical events that may not be immediately life threatening or 
result in death or hospitalization, but that may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 

 
Page 40 of 52 
12.1.3 
Unexpected Adverse Event 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (eg, Investigator’s Brochure for an unapproved investigational medicinal product). 
12.2 
REPORTING 
12.2.1 
Adverse Events 
Adverse events will be recorded for the duration of a patient’s study treatment, and for up to 
30 days following the last study treatment. All AEs, regardless of causal relationship are to be 
recorded in the source documentation. Only those specified in Section 9.1 are to be recorded in 
the CRF. The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. The diagnosis should be documented as the 
AE/SAE and not the individual signs /symptoms.  
Toxicities will be graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 as linked in Appendix I. The event, and the relationship of each 
event to treatment, will be assessed by the Investigator and recorded on the CRF. Additional 
information about each event, such as treatment required, whether or not therapy had to be 
interrupted or dosages reduced, and eventual outcome will also be recorded on the CRF. 
Pre-existing conditions will be recorded at baseline on the Medical History Form. If a pre-
existing condition does not change, it does not have to be reported as an AE on subsequent 
cycles. 
12.2.2 
Serious Adverse Event  
All SAEs will be reported per Baylor standard operating procedure (SOP) within 24 hours of 
becoming aware of the event. All SAEs will be reported by completing a SAE Report Form and 
emailing the form to the PI. Baylor IRB will be notified via iRIS.  
SAEs will be reported to Lilly as soon as possible and no later than 1 business day of the 
Investigator and/or Institution receiving notification of any serious adverse event experienced by 
a patient participating in the study and receiving study drug. The preferred method of SAE 
reporting is via the Lilly Investigator Initiated Research (IIR) portal:  
https://www.lillyinvestigatorresearch.com  
However, fax is also acceptable to report SAEs to the local safety representative using the 
following: 
Local fax number: 866-644-1697 
Local telephone number: 800-545-5979 
All SAEs must be documented on the Serious Adverse Event Report Form and on the adverse 
event CRF page. The event term used on the SAE report should match the term in the CRF.  
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the as soon as it is available. For unexpected fatal, life-threatening, or other 
unexpected SAEs, follow-up information must be reported per Baylor SOP.  

 
Page 41 of 52 
12.2.3 
Discontinuation of Patient 
Discontinuation of a patient on study for the occurrence of a serious or unexpected AE 
associated with the use of the study medication should be reported to the PI and Project 
Manager. 
12.3 
PREGNANCY 
Patients of child-bearing potential participating must agree to use one highly effective (less than 
1% failure rate) method of contraception or use a combination of two effective methods of 
contraception during treatment with study drug and for at least 12 weeks following the last dose 
of study drug. 
Note: Unless not allowed by local regulations, patients of child-bearing potential who are 
abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in a same sex 
relationship (as part of their preferred and usual lifestyle) must agree to either remain abstinent 
or stay in a same sex relationship. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the duration of a trial, and withdrawal 
are not acceptable methods of contraception. 
Women of child-bearing potential participating must test negative for pregnancy prior to 
initiation of treatment as indicated by a negative pregnancy test at the screening visit (prior to 
biopsy) and within 24 hours prior of drug exposure.  
If pregnancy is confirmed in a patient during the course of the study, the patient must be taken 
off treatment and the pregnancy must immediately be recorded on the source documents and 
CRF, and will be reported by completing the Pregnancy Notification Form and emailing the form 
to the PI. Any pregnancy that occurs in a female partner of a male study participant will also be 
immediately recorded on the source documents and CRF and will be reported by completing the 
Pregnancy Notification Form and emailing the form to the PI. In addition, the Investigator must 
report to the Baylor IRB any follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome. Infants will be followed for a minimum of 8 weeks. 
13 PROTOCOL AND DATA DEVELOPMENT 
13.1 
ETHICS 
13.1.1 
Institutional Review Board 
This protocol will be implemented only after review and full approval of the protocol and the 
Patient Informed Consent Form has been obtained from a properly constituted IRB. This written 
approval must be dated and it must clearly identify the protocol, any amendments, the Patient 
Informed Consent Form, and any applicable recruiting materials and subject compensation 
programs approved. 
During implementation of this protocol, the PI is required to send various documents to the IRB 
for review: 
1. Changes to the current protocol. 
2. All protocol amendments and Patient Informed Consent Form revisions. 

 
Page 42 of 52 
3. Required progress reports. 
Particular attention is drawn to the Food and Drug Administration (FDA) regulations regarding 
the IRB. The PI is responsible for the initial and continuing review and approval of the proposed 
clinical study in accordance with these regulations. At least once a year, the IRB will be asked to 
review and re-approve the tissue collection protocol; the request must be documented in writing. 
At the end of the trial, the PI will notify the IRB that the trial has been completed. 
13.1.2 
Patient Informed Consent 
The informed consent should meet the requirements of the latest version of the Declaration of 
Helsinki and any applicable regulations and guidelines. It must be approved by an institutional 
ethics committee/IRB. 
Prior to entry into the trial and before any protocol-required procedures are performed, the 
Investigator must explain the nature of the trial, its intended purpose, and the implications of 
participation to potential patients or to their legal representatives. They will be told about the 
possible risks and benefits, and the possible adverse experiences. They will be informed that 
patients’ participation is voluntary, and that they may withdraw consent to participate at any 
time. They will also be informed that if patients choose not to participate in the trial, alternative 
treatments are available; such refusal will not prejudice further treatment of their disease. 
Potential patients or their legal representatives must be given the opportunity to ask questions 
about the trial protocol and the procedures involved. 
Finally, each patient will be told that his or her records may be accessed by authorized personnel 
and other authorized individuals without violating the patient’s confidentiality, to the extent 
permitted by the applicable laws and/or regulations. By signing the written Patient Informed 
Consent Form, the patient or his or her legal representative is authorizing such access. Following 
this explanation and prior to entry into the trial, the written, dated, and signed Patient Informed 
Consent Form must be obtained from each patient or his or her legal representative; a copy will 
be given to the person signing the form. 
13.1.3 
Confidentiality of Records 
The Investigator is required to retain, in a confidential manner, sufficient information on each 
patient (eg, full name, current address, and social security number) so that the patient may be 
contacted by the FDA, should the need arise. 
13.2 
STUDY RECORDS 
13.2.1 
Documentation 
A log of all patients evaluated for this protocol must be maintained. Patients excluded from 
admission will be provided with a clear explanation of the specific reasons why they have been 
excluded from the study. Patients who are included will be assigned a patient identification 
number. 
For each patient treated with the study drug(s), the Research Coordinator is required to prepare 
and maintain case histories that include all observations and other data pertinent to the 

 
Page 43 of 52 
investigation. This will include all source documents needed to verify the accuracy of all 
observations and other data contained in the CRFs on each study patient. 
The Investigator or his/her designee is required to retain the records related to the trial for a 
period of 2 years following the date a marketing application is approved for the indication being 
investigated. If no application is to be filed or if the application is not approved for such 
indication, the records must be retained until 2 years after the investigation is discontinued and 
the regulatory agencies are notified. 
13.2.2 
Case Report Form Procedures 
Data will be entered at the site using the protocol CRF. The Investigator or his/her designee is 
responsible for recording all data relating to the trial on the CRFs. The Investigator must verify 
that all data entries on the CRFs are accurate and correct. CRFs must be completed within 
15 calendar days of the end of each cycle and within 15 calendar days following completion of 
study therapy. 
13.3 
MODIFICATION OF PROTOCOL 
Any changes to this protocol that affect study objectives, study design, study procedures, patient 
population, or significant administrative procedures will require a formal amendment to the 
protocol. Any proposed protocol amendments must be sent in writing to the applicable IRB. 
Prior to implementation, an amendment must be agreed upon by the PI and approved by the IRB. 
General administrative changes to the protocol are minor corrections and/or clarifications that do 
not affect the manner in which the study is to be conducted. Such administrative changes will be 
agreed upon by the PI and will be documented in a memorandum. The applicable IRB will be 
notified of administrative changes according to applicable IRB guidelines.  

 
Page 44 of 52 
14 REFERENCES 
1. Breast Cancer: Prevention and Control. World Health Organization. Available at: 
http://www.who.int/cancer/detection/breastcancer/en/index1.html. Accessed May 18, 
2018. 
2. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V2.2015. National 
Comprehensive Cancer Network Web site. 
http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 18, 2018. 
3. Ma CX, Luo J, and Ellis MJ. Molecular profiling of triple negative breast cancer. Breast 
Dis. 2010;32:73-84. 
4. Hudis CA, and Gianni L. Triple-negative breast cancer: an unmet medical need. 
Oncologist. 2011;16(Suppl 1):1-11. 
5. Prat A, et al. Molecular features of the basal-like breast cancer subtype based on BRCA1 
mutation status. Breast Cancer Res Treat 14:185-191, 2014. 
6. Helleday T. Homologous recombination in cancer development, treatment and 
development of drug resistance. Carcinogenesis 31:955-960, 2010.  
7. Tobin L, et al. Targeting abnormal DNA repair in therapy-resistant breast cancers. Mol 
Cancer Res 10: 96-107, 2012. 
8. Brand TM, et al. Nuclear EGFR as a molecular target in cancer. Radiother Oncology 
108:1-18, 2014 
9. Burga LN, et al. Loss of BRCA1 leads to an increase in epidermal growth factor receptor 
expression in mammary epithelial cells, and epidermal growth factor receptor inhibition 
prevents estrogen receptor-negative cancers in BRCA1-mutant mice. Breast Cancer Res 
13:R30, 2011. 
10. Gil del Alcazar CR, et al. Inhibition of DNA double-strand break repair by the dual 
PI3K/mTOR inhibitor NVP-BEZ-235 as a strategy for radiosensitization of glioblastoma. 
Clin Ca Res 20:1235, 2014. 
11. Bendell, J, et al. A phase I study of the sachet formulation of the oral dual PI3K/mTOR 
inhibitor BEZ-235 given twice daily (BID) in patients with advanced solid tumors. Invest 
New Drugs 33:463, 2015. 
12. Musa F, et al. Dual mTORC1/2 inhibition as a novel strategy for the resensitization and 
treatment of platinum-resistant ovarian cancer. Mol Cancer Ther 15(7):1557-1567, 2016. 
13. Courtney KD, et al. The PI3K pathway as drug target in human cancer. J Clin Oncol 
28(6):1075-1083, 2010. 
14. Smith MC, et al. Characterization of LY3023414, a novel PI3K/mTOR dual inhibitor 
eliciting transient target modulation to impede tumor growth. Mol Cancer Ther Epub 
ahead of print, 2016. 
15. Moore KN, et al. A phase I first-in-human dose study of the dual PI3K/mTOR inhibitor 
LY3023414 (LY) in patients (pts) with advanced cancer. J Clin Oncol 
33(15 suppl):11075, 2015. 

 
Page 45 of 52 
16. Sen T, et al. CHK1 inhibition in small cell lung cancer produces single-agent activity in 
biomarker-defined disease subsets and combination activity with cisplatin or olaparib. 
Cancer Res May 10, 2017 E-pub ahead of print. 
17. Shibata H, et al. Response of subtype specific human breast cancer-derived cells to PARP 
and Chk1 inhibition. Cancer Sci 102(10):1882, 2011. 
18. Barker HE, et al. CHK1 inhibition radiosensitizes head and neck cancers to paclitaxel-
based chemoradiotherapy. Mol Cancer Ther 15(9):2042, 2016. 
19. Duan W, et al. Fanconi anemia repair pathway dysfunction, a potential therapeutic target 
in lung cancer. Front Oncol 4(368):1, 2014. 
20. Chen CC, et al. CHK1 inhibition as a strategy for targeting Fanconi anemia (FA) DNA 
repair pathway-deficient tumors. Molecular Cancer 8:24, 2009. 
21. Karzai F, et al. A phase II study of the cell cycle checkpoint kinases 1 and 2 (CHK1/2) 
inhibitor (LY2606368; prexasertib) in sporadic triple negative breast cancer (TNBC). 
Annals of Oncology 27 (6): 68, 2016. 
22. Lee J-M, et al. Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA 
wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept 
phase 2 study. Lancet Oncol 19:207-215, 2018. 
23. Hong D, et al. A phase 1b study of prexasertib, a checkpoint kinase (CHK1) inhibitor, 
and LY3023414, a dual inhibitor of class I phosphatidylinositol 3-kinase (PI3K) and the 
mammalian target of rapamycin (mTOR) in patients with advanced solid tumors. J Clin 
Oncol 37, no. 15_suppl (May 20, 2019) 3091-3091. 
24. O’Shaughnessy J, et al. Dual inhibition of DNA double strand break repair and PI3K with 
BEZ-235 to sensitize refractory metastatic triple negative breast cancer to cisplatin/nab 
paclitaxel in a patient with an exceptional response. ASCO Breast Cancer Symposium, 
abst 156, 2015. 
25. Allison KH, et al. Estrogen and progesterone receptor testing in breast cancer: 
ASCO/CAP guideline update. J Clin Oncol 38:1346-1366, 2020. 
26. LY3023414 Investigator’s Brochure, September 28, 2017. 
27. Prexasertib (LY2606368) Investigator’s Brochure, April 18, 2019. 
 

 
Page 46 of 52 
Appendix I 
NCI Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.0 
Publish Date: May 28, 2009 
 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE)  
Version 4.0 
 
As of May 28, 2009 (v4.03: June 14, 2010), NCI has edited version 4.0 of the Common 
Terminology Criteria for Adverse Events. These may be obtained at the following web link 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
 
 

 
Page 47 of 52 
Appendix II 
Schedule of Assessments  
Assessment 
 
Prestudy 
 
As per 8.1 
During Treatment  
on Day 1 prior to each 
cycle, unless otherwise 
specified  
As per 8.2 
End of 
Treatment  
up to 30±2 days 
following 
As per 8.3 
Follow-up  
every 3 months for 1 
year from the date of 
last treatment; 
research data only 
As per 8.4 
Informed consent 
 
 
 
 
Signed patient authorization (HIPAA) 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
Complete medical history 
Within 4 weeks prior to 
registration (PTR) 
 
 
 
Complete physical examination 
(including vital signs, height, and 
body weight) 
Within 4 weeks PTR 
 
 
 
Brief medical history 
 
 
 
 
Brief physical exam (vitals, weight) 
 
 
 
 
Assessment of ECOG PS 
Within 4 weeks PTR 
 
 
 
Assessment of conmeds  
Within 4 weeks PTR 
 
 
 
CBC with differential and platelet 
count 
Within 4 weeks PTR 
1 
 
 
Complete metabolic profile (CMP) 
Within 4 weeks PTR 
1 
 
 
Mg and P 
Within 4 weeks PTR 
1 
 
 
HbA1c 
Within 4 weeks PTR 
1 
 
 
Fasting serum glucose 
Within 4 weeks PTR 
1 
 
 
Serum pregnancy test 
Within 7 days PTR 
 
 
 
ECG 
Within 4 weeks PTR 
2 
 
 
Clinical assessment of disease 
Within 4 weeks PTR 
 
 
 
Radiological assessment of disease  
Within 8 weeks PTR 
As clinically indicated 
 
As clinically indicated 
Assessment of other lesions 
Within 4 weeks PTR 
To confirm CR 
 
 
Toxicity/AE 
 
 
 
For 30 days following 
last dose 
Research biopsies 
Prior to the first day of 
treatment 
After Cycle 2 or 
physician’s discretion3 
 
 
Whole blood (40 mL) 
 
After Cycle 2 or 
physician’s discretion3 
 
 
Patient diaries 
 
 
 
 
Survival, relapse or PD, additional 
therapy 
 
 
 
 
1 Day 1 and Day 15 of each 28-day cycle 
2 A pre-dose ECG (within 10 minutes of beginning prexasertib infusion) must be obtained on Cycle 1 and Cycle 2. A post-dose ECG (within 10 minutes of ending 
prexasertib infusion) must be obtained on Cycle 1 and Cycle 2. Additional ECG may be obtained if clinically indicated. NOTE: it is preferred to complete the post-
dose ECG upon completion of the prexasertib infusion, but prior to LY3023414 dosing. 
3 Any time after the completion of Cycle 2 of the treatment combination, or at the physician’s discretion. 
 
 
 

 
Page 48 of 52 
Appendix III 
ECOG Performance Status Scale 
Grade  
Description 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of light or sedentary nature—(eg, light 
housework or office work) 
2 
Ambulatory and capable of all self care, but unable to carry out 
any work activities; up and about > 50% of waking hours 
3 
Capable only of limited self-care, confined to bed or chair 
>50% of waking hours 
4 
Completely disabled; cannot carry out any self care; totally 
confined to bed chair 
5 
Dead 
 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982; 5:649-655. 

 
Page 49 of 52 
Appendix IV 
Research Biopsies and Blood Collection 
 
Tissue Collection Guidelines for Snap Freezing Tissue for Storage 
Tissue will be snap frozen according to the Biospecimen and Project Management Core (BPM) 
protocol. Briefly, immediately after biopsy, tissue will be placed in a screw-capped cryovial, and 
submerged in liquid nitrogen for rapid freezing and preservation of tissue. Tissue must be 
transported to the Core in the Baylor Charles A. Sammons Cancer Center on the 6th floor on dry 
ice. Tissue will then be stored in -80°C freezer until further use. 
 
Blood Collection Guidelines 
I.  Collections at Clinical Site 
a. Blood: Collect 4 tubes of whole blood in 10 mL purple-top EDTA hematology tubes 
(processing as soon as possible, <1 hour). 
 
II.  Further Processing 
a. Buffy Coat isolation per BPM Core standard protocol, and store at -80°C as usual. 
 
III. Kit contents 
 
1.  Four barcoded labels for 10 mL purple top EDTA hematology tubes 
 
2.  Four to 6 externally threaded cryovials with barcoded labels  
 
3.  Consent form 
 
 
 
 

 
Page 50 of 52 
Appendix V 
Patient Diary for LY3023414 administration and Treatment Side Effects 
 
Patient Diary 
 
 
Patient:  
 
 
 
 
Dates:  
to 
 
 
LY3023414 should be taken twice a day, about 12 hours apart, every day. LY3023414 should be taken with food, although it is not 
required. You should take your study drug at about the same times each day, and not take more than what is prescribed. You must 
swallow the study drug whole and not chew it or open the capsule before swallowing. Keep out of reach of children and do not give 
to any other person. Store the bottle within the temperature range stated on the label. 
 
When you take your study medication, write the date and time taken in each of the corresponding boxes. If you miss a dose of 
LY3023414, you should take the dose as soon as possible, but not less than 6 hours before the next dose is due. If the next dose is 
due within 6 hours, you should skip the missed dose and take the next dose as scheduled. Put an “X” in the appropriate boxes on a 
day that you did not take LY3023414 (missed dose). TAKE YOUR NEXT DOSE AT THE NEXT SCHEDULED TIME. 
 
Please remember to bring the medication bottles and any remaining medication with you to your next study visit or as instructed by 
the study staff. Please also bring this diary. 
 
On the second page, please record any side effect you think you may be having during treatment. Please show this diary to your 
study coordinator at each visit. 
 
 
 
 
 

 
Page 51 of 52 
Dosing Diary: 
 
 
 
 
 
 
Day of the Week: 
 
Date: 
 
 
 
 
 
 
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
LY3023414 
Dose: 
mg
mg
mg
mg 
mg
mg
mg
Dose Times 
AM 
 
 
 
 
 
 
 
PM 
 
 
 
 
 
 
 
Day of the Week: 
 
Date: 
 
 
 
 
 
 
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
LY3023414 
Dose: 
mg 
mg
mg
mg 
mg
mg
mg 
Dose Times 
AM 
 
 
 
 
 
 
 
PM 
 
 
 
 
 
 
 

 
Page 52 of 52 
Side Effects Diary: 
 
1 
Nausea 
6 
Rash 
2 
Vomiting 
7 
Mouth Sores 
3 
Diarrhea 
8 
Constipation 
4 
Fatigue 
9 
Other (specify) 
5 
Loss of Appetite 
 
 
 
 
Side Effects 
Day 
Time(s) 
Treatment 
Time Taken 
Result