Conditions: Endometrial Cancer Recurrent Endometrial Cancer
Keywords: LY3023414 15-079 Persistent Endometrial Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the effectiveness of LY3023414 in treating the participants type of cancer and to determine the types and severity of side effects caused by treatment with LY3023414.

Detailed description:

Arms:
arm 1: This is an MSKCC investigator-initiated, single-center, non-randomized, open-label, phase II study to evaluate the activity of LY3023414 dosed at the RP2D of 200 mg orally twice daily in patients with recurrent or persistent endometrial cancer.

Interventions: intervention 1: LY3023414
Intervention descriptions: intervention 1: Enrolled patients will take LY3023414 200 mg orally twice a day. Each cycle will be 21 days in duration. Patients will receive study treatment until disease progression, intolerable toxicity, elective withdrawal from the study, study completion, or study termination

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
Page 1 of 45 
 
 
 
 
 
 
 
 
 
Single-Arm, Open-Label,  Phase II Study of LY3023414 for the Treatment of Recurrent 
or Persistent Endometrial Cancer 
MSK PROTOCOL 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Vicky Makker, MD 
Medicine 
Co-Principal  Investigator(s)/Department: 
Dmitriy Zamarin, MD, PhD 
Medicine 
 
 
Investigator(s)/Department: 
Carol Aghajanian, MD 
Medicine 
Seth Cohen, MD 
Medicine 
Claire Friedman, MD 
Medicine 
Angela Green, MD 
Medicine 
Rachel Grisham, MD 
Medicine 
Robin Guo, MD 
Medicine 
Martee Hensley, MD, MSc 
Medicine 
Jason Konner, MD 
Medicine 
Chrisann Kyi, MD 
Medicine 
Ying Liu, MD 
Medicine 
Roisin O’Cearbhaill, MD 
Medicine 
Paul Sabbatini, MD 
Medicine 
Alison Schram, MD 
Medicine 
William Tew, MD 
Medicine 
Elizabeth Butler, PA 
Medicine 
Jessica Gahres, PA 
Medicine 
Katy Nickolaus, PA 
Medicine 
Chelsea Semrau, PA 
Medicine 
Viola Chitiyo, RN 
Nursing 
Vania Hom, RN 
Nursing 
Krysten Soldan, RN 
Nursing 
Sara Weissblum, RN 
Nursing 
Mila Gorsky, MD 
Medicine 
Louise Ligresti, MD 
Medicine 
Janet Cogswell, RN 
Nursing 
Karen Dougherty, APN 
Nursing 
Stuart Lichtman, MD 
Medicine 
Sarah Schweber, MD 
Medicine 
Steven Sugarman, MD 
Medicine 


Page 2 of 45 
 
 
 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
Wanqing Iris Zhi, MD, PhD 
Jacqueline Bromberg, MD, PhD 
Loren Michel, MD 
Serena Wong, MD 
Michelle Abboud, NP 
Nicole Heinz, RN 
Raylene Langish, RN 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Oscar Lahoud, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Chau Dang, MD 
Rachel Sanford, MD 
Maureen Kennedy, RN 
Alexis Leitenberger, NP 
Sheri Mar-Chaim, RN 
Gloria Wasilewski, RN 
Alexia Iasonos, PhD 
Jean Torrisi, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Biostatistics 
Radiology 
Consenting 
Professional(s)/Department: 
Carol Aghajanian, MD 
Seth Cohen, MD 
Claire Friedman, MD 
Angela Green, MD 
Rachel Grisham, MD 
Robin Guo, MD 
Martee Hensley, MD, MSc 
Jason Konner, MD 
Chrisann Kyi, MD 
Ying Liu, MD 
Vicky Makker, MD 
Roisin O’Cearbhaill, MD 
Paul Sabbatini, MD 
Alison Schram, MD 
William Tew, MD 
Dmitriy Zamarin, MD, PhD 
Mila Gorsky, MD 
Louise Ligresti, MD 
Stuart Lichtman, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 


Page 3 of 45 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
 
 
 
 
 
 
 
Sarah Schweber, MD 
Medicine 
Steven Sugarman, MD 
Medicine 
Wanqing Iris Zhi, MD, PhD 
Medicine 
Jacqueline Bromberg, MD, PhD 
Medicine 
Loren Michel, MD 
Medicine 
Serena Wong, MD 
Medicine 
Arlyn Apollo, MD 
Medicine 
Pamela Drullinsky, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Oscar Lahoud, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Chau Dang, MD 
Medicine 
Rachel Sanford, MD 
Medicine 
 
 
Please Note: A Consenting Professional musthave completed the mandatory Human Subjects Education 
and Certification Program. 
 
OneMSK  Sites 
Manhattan, NY 
All Protocol Activities 
Basking Ridge, NJ 
All Protocol Activities 
Commack, NY 
All Protocol Activities 
Monmouth, NJ 
All Protocol Activities 
Nassau, NY 
All Protocol Activities 
Westchester, NY 
All Protocol Activities 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Page 4 of 45 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .................................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................................6 
3.0 
BACKGROUND AND RATIONALE ......................................................................................................7 
Safety Pharmacology............................................................................................................................... 11 
Nonclinical Pharmacokinetics/Pharmacodynamics ................................................................................ 12 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .......................................................................... 16 
4.1 
Design .................................................................................................................................... 16 
4.2 
Intervention ................................................................................................................................. 17 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................................... 17 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................................................... 19 
6.2 
Subject Inclusion Criteria .............................................................................................................. 19 
6.3 
Subject Exclusion Criteria .............................................................................................................. 20 
7.0 
RECRUITMENT PLAN ......................................................................................................................... 21 
8.0 
PRETREATMENT EVALUATION ............................................................................................................ 22 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................................... 23 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .......................................................................... 24 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................................... 25 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................................................... 28 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................................... 34 
14.0 
BIOSTATISTICS ..................................................................................................................................... 35 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ............................... 36 
15.2 
Research Participant Registration ................................................................................................. 37 
15.3 
Randomization ............................................................................................................................. 37 
16.1 
DATA MANAGEMENT ISSUES ........................................................................................................... 37 
16.2 
Quality Assurance ........................................................................................................................... 38 
16.3 
Data and Safety Monitoring ....................................................................................................... 39 
17.1 
PROTECTION OF HUMAN SUBJECTS .................................................................................................... 40 
17.2 
Privacy ............................................................................................................................................. 40 
17.3 
Serious Adverse Event (SAE) Reporting .......................................................................................... 40 
17.2.1      ..........................................................................................................................................41 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................................... 42 


Page 5 of 45 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
 
 
19.0 
REFERENCES ........................................................................................................................................ 42 
20.0 
APPENDICES ..................................................................................................................................... 44 


Page 6 of 45 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
 
 
 
 
 
1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
 
Patients with recurrent or persistent  endometrial adenocarcinoma  with the following histologic 
epithelial  cell types are eligible: endometrioid  adenocarcinoma,  serous adenocarcinoma, 
undifferentiated  carcinoma,  clear cell adenocarcinoma,  mixed epithelial  carcinoma, 
adenocarcinoma  not otherwise  specified (N.O.S.), mucinous  adenocarcinoma,  squamous cell 
carcinoma,  transitional  cell carcinoma, and carcinosarcoma. 
 
Patients must have had at least one but no more than four prior chemotherapeutic  regimens  for 
management  of endometrial  carcinoma (including adjuvant chemotherapy).  Initial treatment  may 
include  chemotherapy,  chemotherapy and radiation therapy, and/or consolidation/maintenance 
therapy, and chemotherapy administered  in conjunction  with primary radiation as a radio-sensitizer 
WILL be counted as a systemic  chemotherapy regimen. 
 
Patients must have PI3K pathway activation defined  as EITHER of the following: 
 
1. Genomic  alteration resulting in loss of PTEN function including a) whole or partial gene 
deletion,  frame shift mutations,  or non-sense mutations.  Missense mutations  in PTEN will 
not be considered qualifying. 
2. A previously characterized  activating mutation  in any component of the pathway including: 
PIK3CA, AKT1, PIK3R1, PIK3R2, mTOR 
 
Patients must also not have a known concurrent activating  RAS/RAF mutation  or loss of function 
alternation in NF1 of NF2 resulting in MAP kinase pathway activation.  Any mutational  profiling 
performed in a CLIA laboratory either as routine standard of care or as part of a dedicating 
genomic  profiling study such as MSKCC IRB# 12-245 will be accepted. 
 
LY3023414 will be administered  orally at the Recommended  Phase 2 Dose (RP2D) of 200mg BID 
on a continuous  basis. One cycle equals 3 weeks. Treatment  will continue  until progression, 
intolerance,  or withdrawal,  study completion,  or study termination.  Tumor evaluations  will occur 
every 2 cycles. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 
PRIMARY OBJECTIVES 
 
To assess the activity of LY3023414 in patients with PI3K pathway activated  recurrent or 
persistent endometrial  cancer as measured by the best overall response rate as determined  by 
RECIST 1.1. 


Page 7 of 45 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
 
 
 
 
 
2.2 
SECONDARY OBJECTIVES 
 
The secondary objectives of this study are as follows: 
 
1. To determine  the clinical benefit  rate (CBR) of LY3023414 therapy, defined as the 
percentage of patients with complete response (CR) + partial response (PR) + stable 
disease (SD) ≥12 weeks from the start of treatment. 
2. To determine  progression free survival  (PFS), defined  as the duration of time from start of 
treatment to time of recurrence, progression,  or death due to any cause, whichever  occurs 
first. . 
3. To determine  overall survival  (OS), defined as the duration of time from start of treatment 
until the date of death due to any cause. 
4. To determine  the duration of response (DOR) of LY3023414 therapy, defined as the time 
from which measurement  criteria are met for CR or PR (whichever  status is recorded first) 
until the first date of documented disease progression. 
5. To assess the safety profile and tolerability of LY3023414 therapy in patients with PI3K 
activated  recurrent/persistent  endometrial  cancer. 
 
2.3 
EXPLORATORY OBJECTIVES 
 
1. For patients who have not already had their tumors molecularly profiled using the 
MSK-IMPACT platform,  pretreatment  archival tumor tissue will be obtained for this 
purpose. Consent for this testing,  to be performed in the CLIA laboratory, will be 
obtained through a companion study MSKCC IRB# 12-245. 
2. Serial pre-, on- and post-treatment blood samples will be collected for cell-free tumor 
DNA analysis  and the results descriptively correlated to clinical outcome. 
3. Patients who respond to therapy and then progress will be offered consent to MSKCC 
IRB# 12-245 Part B in order to obtain post-progression material for molecular  profiling 
in order to determine  the mechanism(s)  underlying acquired resistance. 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
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,  and in the development  of 
malignant  disease (Bjornsti and Houghton 2004; Samuels and Ericson 2006). 


Page 8 of 45 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
 
 
 
 
 
 
 
 
PI3K phosphorylates  phosphatidylinositol-4,5-bisphosphate  (PIP2) to generate 
phosphatidylinositol-3, 4, 5-trisphosphate,  a lipid second messenger, which binds the 
serine/threonine  kinase AKT, and its activating kinase, 3-phosphoinositide-dependent  kinase 1 
(PDK-1) (Corvera and Czech 1998), which partially activates AKT.  AKT controls cell survival, 
proliferation,  and invasion via numerous  downstream targets, including mTOR (Stahl et al. 2004; 
Cheng et al. 2005; Meier et al. 2005).  The mTOR kinase exists in 2 complexes,  mTORC1 and 
mTORC2.  The mTORC1 complex is activated downstream of PI3K/AKT signaling,  stimulates 
protein translation by activating p70S6 kinase and eIF4E, and is disrupted by rapamycin and 
analogues  (rapalogs).  The mTORC2 complex completes the activation of AKT by 
phosphorylating AKT at the critical serine-473 residue.  Pharmacological  inhibition of 
PI3K/mTOR blocks tumor growth and survival  signaling in a variety of different  tumor xenograft 
models (Courtney et al. 2010).  Inhibition of PI3K/mTOR also blocks the metabolic  actions of 
insulin,  including glucose transport and glycogen synthesis,  resulting in increased blood glucose 
and compensatory release of insulin (and C-peptide) from pancreatic cells (Katso et al. 2001). 
Hence, it is important  to evaluate in the clinic  the adverse events (AEs) on such metabolic 
pathways when novel PI3K/mTOR inhibitors  are being investigated. 
 
Targeting the PI3K/mTOR pathway represents an attractive strategy in patients with tumor types 
harboring an activating alteration of the PI3K/mTOR signaling pathway.  There are several 
mechanisms  that lead to aberrant activation of this pathway including mutations  of growth factor 
receptors, PIK3CA, or loss of the tumor suppressor, PTEN (Stambolic  et al. 1998; Courtney et al. 
2010). In addition, PI3K amplification and activating mutations  in AKT, PDK1, RAS, tuberous 
sclerosis protein 1 and 2 (TSC1/2), and mTOR have been identified  as mechanisms  of 
PI3K/mTOR pathway activation (Samuels  and Ericson 2006). Frequent activating aberrations of 
PI3K/mTOR signaling have been reported amongst others for breast cancer, mesothelioma,  non- 
Figure 1. 
PI3K/mTOR  signaling pathway in cancer. 
Source:  Adapted from Courtney et al 2010. 


Page 9 of 45 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
 
 
 
 
 
small cell lung cancer (NSCLC), and endometrial  cancers (Opitz et al. 2008; Courtney et al. 2010; 
Miller  et al. 2011; Varghese et al. 2011).   To date, no dual PI3K/mTOR inhibitor  has been 
approved for therapy.  However, several molecules  are currently under investigation in Phase 1 
and 2 clinical trials as monotherapy or in combination with standard of care therapies. 
Monotherapy with PI3K/mTOR inhibitors  is of interest in tumor types with a particular  high 
incidence  of aberrant PI3K pathway activation. 
 
Endometrial  Carcinoma  Background 
 
Endometrial cancer is the second leading cause of death from gynecologic  cancer with an 
estimated 8,590 women dying in the United Stated annually (Siegel et al. 2014)). Carboplatin and 
paclitaxel is the standard first-line  treatment regimen (Miller  et al. 2012) for advanced recurrent or 
persistent disease. There are no FDA approved treatments  for patients who progress on first line 
therapy. Response rates for commonly used off label therapies including liposomal doxorubicin, 
topotecan, weekly paclitaxel,  and bevacizumab  range between approximately 0-10% (Muggia  et 
al. 2002; Miller  et al. 2002; Lincoln et al. 2003; Aghajanian et al. 2011). As a result, there is 
tremendous  opportunity for the development  of rationally therapeutic  agents in the 
recurrent/persistent  endometrial cancer space. Detailed  genomic  characterization of endometrial 
cancer has identified  the phosphatidylinositol  3-kinase/mammalian target of rapamycin 
(PI3K/mTOR) pathway as central to endometrial cancer pathogenesis.  The TCGA found the PI3K 
pathway to be activated in 84% of primary surgical endometrial  cancer specimens  (Figure  2, 
Cancer Genome Atlas Research Network, 2013). 
 
 
 
 
 
Inactivation of the PTEN tumor-suppressor  gene is the most common genetic defect in endometrial 
cancers and is present in 30−83% of tumors (Mutter et al. 2000; Oda et al. 2005). Mutations in the 
catalytic  p110α subunit  of PI3K are found in approximately 30-40% of endometrial cancers, and 
these mutations  are most frequent in tumors that also bear phosphatase and tensin homolog  
(PTEN) mutations  (Hayes et al. 2006; Salvesen et al. 2009).  With regard to endometrial  cancer 
subtypes, PIK3CA mutations  are found in 15% of serous cancers (Hayes et al. 2009). Somatic 
mutations  in the PIK3R1 have been found in 43% of endometrioid  (Type I) endometrial cancer  
and 12% of non-endometrioid  (Type II) endometrial cancer (Cheung et al. 2011; Urick et al. 
2011). The PIK3R2 (p85α is also frequently mutated (Cheung et al. 2011). Mutant p85 α proteins 
are believed to activate the PI3K pathway as five of seven different  p85 α mutants  expressed in 
cell lines were associated with increased p-AKT levels  compared to cells expressing wild- type 
p85α (Urick et al. 2011). 
Figure 2: PI3K Pathway Activation in Endometrial  Cancer 
Source: Cancer Genome Atlas Research Network, Nature 2013 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
Page 10 of 45 
 
 
 
 
 
 
Dual PI3K/mTOR  Inhibition  Endometrial  Cancer: 
The results of a single  arm phase II study of GDC-0980 were presented at the ASCO 2014 Annual 
Meeting (Makker et al. 2014, Abstract 5513). MSKCC lead enrollment  to this multicenter  study. 
Anti-tumor  activity was observed in a high proportion of evaluation  subjects with the majority of 
subjects with tumor regression harboring an identifiable  mutation in PTEN, PIK3CA, AKT1, 
PIK3R1, or PIK3R (Figure 3). 
 
 
 
 
 
 
 
The rate of PI3K pathway activation among all enrolled subjects was 67%, approximately 20% 
lower than the rate reported by the TCGA series that includes  a high proportion of patients who are 
likely to be surgically cured. Moreover, 7/56 (12.5%) of patients harbored concurrent  KRAS 
mutations  which would be predicted to confer resistance to dual PI3K/mTOR inhibition.  The 
observations  of a lower rate of PI3K pathway activation in recurrent endometrial cancer patients as 
well as concurrent KRAS mutations  support the need to prospectively screen patients with a 
comprehensive  genomic  assay prior to clinical trial enrollment.  Despite a high proportion of 
objective responses in evaluable  patients, clinical  benefit to GDC-0980 in this study was limited 
by poor tolerability.  Rates of Grade ≥3 hyperglycemia  were 9/13 (69%) and 15/43 (35%) in 
Figure 3: Waterfall Plot and Biomarker Correlates of GDC-0980 in Endometrial  Cancer 
Source: ASCO 2014 Annual Meeting,  Makker V, Abstract 5513 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
Page 11 of 45 
 
 
 
 
 
diabetics and non-diabetics,  respectively.  As a result, the median duration of treatment  for 
diabetics on study was only 36 days. Poorly crafted eligibility criteria likely played an important 
role in this outcome as diabetics with an HgA1c ≤ 8.5 g/dL were permitted to enroll. Of note, the 
frequency of severe hyperglycemia  observed to date in the first-in-human Phase I study of 
LY3023414 has been much lower than GDC-0980 (see Investigational  Brochure), suggesting 
LY3023414 will be better tolerated in this patient population. 
Tumor Genetic Profiling  at MSKCC 
In January 2014 MSKCC received New York State CLIA-approval for a next generation Ilumina 
HiSeq exon-capture based platform (“MSK-IMPACT”) which offers complete coverage of 341 
cancers related genes and can identify base substitutions,  indels, copy number alterations  and 
select translocations  (see gene list in supplied  Appendix for IRB 12-245). Importantly,  MSK- 
IMPACT covers all genes relevant to the PI3K pathway including PTEN, PIK3CA, PIK3R1, 
PIK3R2, AKT1, and mTOR as well as genomic  alterations  which would be expected to confirm 
resistance to PIK3CA/mTOR inhibitors  including those in the MAPK pathway (RAS, RAF, 
MAP2K, NF1, NF2). All metastatic  endometrial cancers are consented to an IRB-approved center 
wide genomic  profiling protocol and screened via the CLIA-approved MSK-IMPACT and the 
results entered into the medical record. As a result, MSKCC is uniquely positioned  to 
prospectively identify PI3K pathway activated endometrial cancer patients early in their disease 
course. 
LY3023414 Summary 
 
LY3023414 is an orally available,  potent selective  inhibitor  of the class I PI3K isoforms,  mTOR, 
and DNA-PK. LY3023414 binds the adenosine  triphosphate  (ATP) active site of PI3K to  
competit ively inhibit  phosphorylation of phosphatidylinosito l-4,  5-bisphosphate at low nanomolar 
concentrations.   LY3023414 has demonstrated inhibitory activity against PI3K and mTOR, 
antiproliferat ive  activity,  and cell-cycle  effects in cultured  cancer cells.   LY3023414 achieves 
good oral exposure and displayed in vivo target inhibit io n in xenograft  tumors, as well as efficacy 
in 3 tumor  xenograft  models,  a transgenic  mutant PI3K-driven leukemia  model,  and multiple 
patient derived xenografts,  including  mesothelio ma  and squamous non-small cell lung cancer 
(NSCLC).  In the transgenic  mutant PI3K-driven leukemia  model, combination  studies with 
LY3023414 and standard of care agents, demonstrated  synergy  with LY3023414 plus 
gemcitabine  or paclitaxel.   Combinat ions  of LY3023414 with rapamycin  were synergistic  in 
U87MG and NCI-H1975 xenograft  models. 
 
Safety Pharmacology 
Nonclinical Toxicology 
LY3023414 was evaluated  in nonclinical toxicology studies up to 1 month in duration using 
daily oral dosing in rats and dogs to characterize  the toxicity.  Based on results from nonclinical 
studies in the rat and the dog, toxicities  patients  may experience  include  (but are not limited  to) 
gastrointestinal  toxicity,  bone marrow and lymphoid  organ toxicity (decreases in lymphocytes), 
and sores/scabbing of the skin. Pharmacologic effects of PI3K/mTOR inhibition related to glucose 
metabolism have also been observed, including hyperinsulinemia, hyperglycemia, and QT interval 
prolongation  in nonclinical studies.   In a rat embryo-fetal developmental pilot study of 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
Page 12 of 45 
 
 
 
 
 
LY3023414, embryo-fetal lethality was seen along with an increase in fetal and litter  incidence  of 
external,  visceral, and skeletal malformations. 
 
For additional details on nonclinical toxicology data, see Section 5.2.1 of the Investigator’s 
Brochure  (IB). 
Nonclinical Efficacy Pharmacology  Summary 
LY3023414 is a potent selective  inhibitor  of the class I PI3K isoforms  mTOR and DNA-PK, with 
selectivity in kinase enzyme  assays as an ATP competitive  inhibitor  of PI3K (Ki 8.5nM). 
LY3023414 demonstrated  inhibitory activity against PI3K/mTOR pathway targets in vitro and in 
vivo as measured by phosphoprotein levels from cultured  cells and tumor xenografts.  LY3023414 
showed antiproliferative  and cell-cycle  arresting effects in cultured  cancer cells, and anti- 
angiogenesis  activity via inhibition of in vitro vascular cord formation.   LY3023414 has excellent 
solubility and oral bioavailability across a wide pH range, allowing for simple  suspension 
formulations  to be used for oral administration in nude mice.  In xenograft  tumor models, 
LY3023414 demonstrated  dose- and time-dependent  target inhibition,  as well as antitumor  efficacy 
in a wide range of tumor models (including renal cancer and non-small cell lung carcinoma 
[NSCLC]).  The mouse pharmacokinetic  (PK)/pharmacodynamics  (PDx) model indicates  a direct 
inhibition of downstream target phosphoproteins  (such as, phospho Akt [pAkt], phospho 70S6K 
[p70S6K]).  LY3023414 has potential for combination with standard of care agents to produce 
synergistic  effects in cell culture and in vivo xenograft  models. 
 
 
Nonclinical Pharmacokinetics/Pharmacodynamics 
The nonclinical PK profile  of LY3023414 was characterized  in mice, rats, and dogs.  Data from 
these studies were used to predict human PK via allometric  scaling.  The predicted mean human 
clearance (CL) is 16.3 L/h (90% CI: 13.5 to 19.9) and the predicted central and peripheral volumes 
of distribution (V) are 61 L (90% CI: 53 to 70) and 1200 L (90% CI: 0 to 12,000), respectively. 
The predicted effective  half-life  (t1/2) in humans  is 2.6 hours with a terminal elimination  t1/2 of 600 
hours, reflecting <8% of the dose.  The predicted bioavailability (74%) allows for once daily (QD) 
or twice daily (BID) oral dosing.  Bioavailability was constant across preclinical  species tested, 
and the predicted efficacious  doses in humans  are below the predicted maximum absorbable dose. 
The in vitro metabolism of LY3023414 was evaluated in rat, mouse, dog, and human liver 
microsomes  and in cryopreserved hepatocytes.  LY3023414 was the major in vitro component 
observed in each species, based on the mass spectrometry (MS) signal.   Metabolism was primarily 
oxidative  (O-desmethyl,  N-desmethyl, and parent + O) in both animals  and humans. No Phase II 
conjugates were identified. 
 
 
Preliminary studies were conducted to evaluate  in vivo metabolism  of LY3023414 in rat plasma, 
bile, urine, and feces and in dog plasma.   In vivo LY3023414 appears to be predominantly cleared 
by oxidative  metabolism as determined  by the major metabolites  detected in rat bile, urine, and 
feces.  LY3023414 was the largest circulating entity in both rat and dog plasma along with 
oxidative  and conjugative  metabolites.   The in vivo results qualitatively correlated well with the in 
vitro results. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
Page 13 of 45 
 
 
 
 
 
Ongoing Studies and Clinical Safety 
 
One Phase I study I6A-MC-CBBA (Study CBBA) of LY3023414 is ongoing.   Study CBBA is a 
multicenter,  nonrandomized,  open-label, First-in-Human  dose escalation  study followed  by cohort 
expansion of oral LY3023414 in patients with advanced and/or metastatic cancer.  Study CBBA 
was designed to evaluate  the safety and tolerability of LY3023414 administered  orally over 21 
days (one cycle). 
 
 
As of 26 September 2014, a total of 47 patients have received LY3023414 in the first-human-dose 
Study CBBA.  Of these patients, a total of 40 patients (83%) experienced  at least 1 possibly study 
drug-related, treatment-emergent  adverse event (TEAE).   The most common possibly LY3023414- 
related AEs reported in at least 10% of patients included  nausea (37.5%), fatigue  (31.3%), 
vomiting (27.1%), diarrhea (16.7%), decreased appetite (14.6%), anemia (14.6%), stomatitis 
(12.5%), and asthenia 10.4%). Most of these events were graded as mild or moderate by the 
investigators. 
 
 
Dose-limiting toxicities  for LY3023414 QD dosing have been reported at 450 mg LY3023414 in 3 
out of 3 patients, including 1 case each of thrombocytopenia  (Grade 4), hypotension (Grade 3), and 
hyperkalemia  (Grade 3).  Therefore, a dose of 325 mg LY3023414 was defined as the maximum 
tolerated dose (MTD) for QD dosing.   For BID dosing,  Dose-limiting  toxicities  (DLTs) were 
observed in 3 out of 4 patients at the 250 mg BID LY3023414 dose in the form of 
hypophosphatemia  (Grade 4), fatigue,  and  mucositis  (Grade 3; all n = 1).  At the next lower dose 
level of 200 mg BID, 1 out of 6 patients experienced a DLT in the form of nausea (Grade 2; n = 
1).  Therefore, a dose of 200 mg LY3023414 was defined as the MTD for BID dosing. 
 
 
At doses up to and including the MTD for QD and BID dosing (n = 31 patients), no study drug 
related Grade 4 AEs have been reported.  Six possibly related Grade 3 AEs have been observed in 
those patients, including 1 case each of fatigue,  hyperglycemia,  hypokalemia,  neutropenia, 
hypomagnesemia,  and anemia (anemia  occurred in a patient entering the study with Grade 2 
anemia). 
 
 
Initial clinical LY3023414 pharmacokinetic/pharmacodynamic  (PK/PD) data showed that 
LY3023414 maximum plasma concentration  (Cmax) and area under the plasma  concentration-time 
curve (AUC∞) increased approximately  dose-proportionally from 20 to 325 mg QD (that is within 
the QD dose range determined  to be safe).  However, the Cmax and AUC∞ increase was greater than 
dose proportional at 450 mg QD (i.e., that is at the dose exceeding the MTD).  LY3023414 PK 
data following repeated BID dosing (dose range of 150 to 250 mg BID) were consistent  with PK 
data following 20 to 325 mg QD. The oral clearance (CL/F) ranged from approximately 77 to 130 
L/hour across the 20 to 325 mg dose range associated with an oral volume  of distribution (V/F) 
ranging from 185 to 315 L in that same dose range.  This clearance and volume  lead to mean half- 
life (t1/2) of 2.07 hours (coefficient  of variation  [CV] = 45%, n = 35), consistent  with the 
prediction. 


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IRB Number: 15-079 A(12) 
Approval date: 16-Jun-2020 
Page 14 of 45 
 
 
 
 
 
The relative  contribution of microsomal CYP-mediated clearance of LY3023414 was studied in 
vitro using human liver  microsomes.   Based on a substrate depletion approach, CYP 3A4 and 
CYP1A2 are responsible  for 82% and 18% of hepatic CYP-mediated clearance of LY3023414, 
respectively.   No in-vivo  data are yet available. 
 
 
The recent data from study CBBA indicate  that LY3023414 is a weak inhibitor  of CYP3A4. 
Concomitant  administration of LY3023414 and midazolam lead to increase in midazolam 
exposure (fold increase: mean 1.459 [CV 30.5 %] [90% CI 1.21 – 1.76]).  Hence LY3023414 may 
lead to increase in exposure of CYP3A4 substrate.  Considering that CYP2C8, not CYP3A4, is the 
most relevant  and major enzyme  responsible  for enzalutamide  clearance and that the inhibitory 
effect of LY3023414 on CYP3A4 is weak, it is not anticipated  that enzalutamide  exposure will be 
significantly increased (i.e. > 1.5 fold change) after coadministration with LY3023414. 
 
 
Biomarker assessment  demonstrated target inhibition as measured by p4EBP1 inhibition in 
peripheral blood mononuclear  cells (PBMC) at LY3023414 dose levels greater or equal to 150 mg 
QD in a dose related manner.  With respect to anti-tumor  activity,  clinical benefit  was observed in 
patients treated on both schedules of LY3023414, including 1 patient with a confirmed  partial 
response according to Response Evaluation Criteria in Solid Tumors (RECIST) and 10 additional 
patients (26.3%) who demonstrated  a decrease in their tumor target lesion as best response to 
LY3023414 monotherapy in the dose-escalation part of Study CBBA. 
Based on the safety and tolerability,  pharmacokinetic/pharmacodynamic  (PK/PD), and preliminary 
activity data outlined  above, the recommended  dose for LY3023414 is 200 mg BID. 
 
Based on results from this study, the safety data for this protocol has been updated. One patient 
was treated until Cycle 2 Day 10 when she presented with coronavirus,  unrelated  to protocol 
treatment. Following this, on Cycle 2 Day 16, the patient was admitted with grade 4 fever, grade 3 
hypokalemia  and acute decline in mental status – treatment  with intravenous  Vancomycin,  Zosyn, 
and Acyclovir  was started. Grade 3 hypokalemia  was attributed  to drug versus secondary to 
malignancy.  Throughout  the hospitalization,  patient was continuously febrile  (grade 1-2) for 7 
days, intermittently febrile  for 2 days, and afebrile  for the remaining 12 days until discharge. 
Treatment  included  intravenous  Vancomycin,  Ceftriaxone,  Ampicillin,  Acyclovir,  and 
Doxycycline.  Infectious  disease workup, urine and blood cultures,  and cerebrospinal fluid  were all 
negative. 
During the hospitalization,  CPK increased to Grade 4 and normalized  within a week. While the 
exact source was not clear, it was felt to possibly be secondary to the persistent fevers. Patient 
subsequently developed grade 4 hyponatremia  was felt to be secondary to SIADH versus cerebral 
salt wasting,  and unlikely secondary to trial drug. Throughout  the hospitalization,  platelets  count 
continued  to decline and on the last day in the hospital,  thrombocytopenia  was grade 4. Hemolytic 
Uremic Syndrome /TTP and hemolysis  were ruled out. Etiology was felt secondary to infection, 
cancer or possibly trial drug related. 
New onset of grade 3 hypertension occurred while hospitalized  as well and was felt to be possibly 
related to her illness  syndrome. 
Etiology of mental status change remained unclear. The neurology team was consulted.  EEG was 
negative  for seizure. MRI of the brain was positive  for white matter changes raising concerning for 


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Approval date: 16-Jun-2020 
Page 15 of 45 
 
 
 
 
 
a demyelinating process such as Multiple  Sclerosis, but overall this did not explain patient’s 
clinical presentation.  EMG and Anti N-methyl-D-aspartate  were negative  and no evidence of 
neuroleptic  malignant  syndrome was found. Patient was treated with empiric  thymine  course and 
finally with 3 doses of Methylprednisolo ne,  which ultimately led to resolution of the fevers and 
improvement  in mental status. Based on all tests and results, the source of fevers and altered 
mental status was felt to be paraneoplastic  versus virus-mediated  versus possibly related to trial 
drug. 
Patient was discharged  to an inpatient  rehabilitation center on 12/4/15 in stable condition. 
 
 
Additional data are available  in the latest Investigator’s  Brochure (IB). 
 
Rationale for LY3023414 in PI3K-Activated Endometrial  Cancer 
 
MSKCC has been instrumental  in the early phase development  of this molecule  and was one of 
only 3 sites to participate  in the first-in-human Phase I study. During the dose escalation portion of 
this study 2/4 endometrial  cancer patients treated at ≥50% of the MTD experienced RECIST tumor 
regressions  of ≥20% (personal communication,  V. Wacheck, Lilly).  Representative  images  and 
tumor marker trends for one patient are shown in Figure 4. This patient has both PTEN loss and 
PIK3R1 mutation and remains on therapy after 7 cycles. MSKCC’s early experience with 
LY3023414 will also help ensure that this early phase asset is managed safely in the context of an 
investigator  initiated  trial 


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IRB Number: 15-079 A(12) 
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Page 16 of 45 
 
 
 
 
 
 
 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
This is an MSKCC investigator- initiated,  single-center,  non-randomized,  open-label, phase 
II study to evaluate the activity of LY3023414 dosed at the RP2D of 200 mg orally twice 
daily in patients with recurrent or persistent endometrial  cancer. The safety and tolerability 
of LY3023414 will also be evaluated. 
 
Each cycle will be 21 days in duration. Patients will receive study treatment until disease 
progression, intolerable toxicity, elective withdrawal from the study, study completion, or 
study termination. 
 
Efficacy  assessments will be performed every 2 cycles from initiation of study 
treatment until disease progression. 
 
Safety will be evaluated  in this study through  the monitoring of all serious and non- 
serious AEs, graded according to the current version National Cancer Institute 
Common Terminology Criteria for Adverse Events 
Figure 4: 


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IRB Number: 15-079 A(12) 
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Page 17 of 45 
 
 
 
 
 
 
4.2 
Intervention 
Eligible  patients will undergo screening and baseline  procedures per the Study Schedule. 
Study inclusion and exclusion criteria will be applied per section 6.0. Enrolled  patients 
will take LY3023414 200 mg orally twice a day. Each cycle will be 21 days in duration. 
Patients will receive study treatment  until disease progression,  intolerable  toxicity, 
elective  withdrawal from the study, study completion,  or study termination 
 
Efficacy  assessments will be performed every 2 cycles from initiation of study 
treatment until disease progression.  Safety will be evaluated  in this study through 
the monitoring of all serious and non-serious  AEs, graded according to the current 
version of the National Cancer Institute  Common Terminology Criteria for Adverse 
Events. 
 
Each dose should be taken with a minimum  of 8 ounces of water. Patients should take the 
morning and evening doses of LY3023414 approximately 12 hours apart (preferably within 
a 10- to 14-hour range). 
 
Patients should not consume food for approximately 1 hour before taking the dose of 
LY3023414.  If a dose is vomited  within one hour of ingestion,  it will be replaced. If 
vomiting occurs more than 1 hour after dosing, it will be considered a complete dose and 
will not be replaced. If a patient misses a dose, the patient should skip that dose and resume 
dosing with the next scheduled dose. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
LY3023414 will be supplied  as 25-, 100-, or 200- mg capsules/tablets  for oral  
consumption.   LY3023414 capsules/tablets  should be stored within the temperature range 
stated on the label.  Investigators  should instruct  patients to store the capsules/tablets  at 
home in the provided container  and to keep out of the reach of children.   Capsules/tablets 
should not be opened, crushed, or dissolved.  LY3023414 will be labeled according to local 
regulatory requirements  and supplied  by the sponsor. 
 
Lilly compound number: 
LY3023414 
Chemical Name (CA Index Name): 
2H-Imidazo[4,5- c]quinolin- 2-one,  8- [5- 
(1-hydroxy-1-methylethyl)-3- 
pyridinyl]-1-  [(2S)-2-methoxypropyl]- 
3-methyl- 
Other Names: 
(S)-8-(5-(2-hydroxypropan-2-yl)pyridin-3-  yl)-1- 
(2-methoxypropyl)-3-methyl-1H- imidazo[4,5- 
c]quinolin-2(3H)-one 
Molecular  weight: 
406.48 
Molecular/Empirical  Formula: 
C23H26N4O3 
Description: 
Practically  white  to light  yellow  solid 
pKa: 
4.92 and 3.75 


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Page 18 of 45 
 
 
 
 
 
 
pH: 
5.79 (10 mg/mL  suspension in water) 
Specific Rotation 
[]436 – 42.09°; []589 17.51° 
Stabilit y: 
The drug substance is stable when stored at room 
temperature. 
Solubilit y: 
Water – Very slight ly  soluble 
Ethanol – Slightly  soluble 
 
Formulation:  The drug product LY3023414 is supplied for clinical  trial use as either 25- 
mg, 100-mg, or 200-mg capsules/tablets. The 25-mg capsules/tablets  are an opaque white 
on the body and cap.  The 100-mg capsules/tablets  are an opaque blue on the body and 
cap.  The 200-mg capsules/tablets  are an opaque orangish-red  color on the body and cap. 
Each capsule/tablet  contains only LY3023414, with no inactive  ingredients. The drug 
product is packaged in bottles and is stable when stored at room temperature conditions 
according to the label. 
 
Labeling: Each bottle of LY3023414 will be labeled in accordance with current FDA and 
specific  national requirements. 
 
Storage condition for LY3022414 is 10-30°C (50-86°F). 
 
 
 
LY3023414 Dosing Information:  After the initial screening visit  and registration in the 
study, patients will receive  LY3023414 twice daily orally at a starting dose of 200mg. 
 
Drug Product Accountability:  Study drug for the study are provided by Eli Lilly and 
Company, Inc. and will be labeled as per the applicable  regulations.   Sites must request 
study drug by submitting an order form directly to the drug depot in order for the study 
drug to be shipped to the site pharmacy.  The Investigator  (or designee) will verify and 
acknowledge receipt of all study drug shipments  by signing and returning all required 
forms. 
 
All clinical  drug supplies must be kept in an appropriate, limited  access, secure place until 
used Drug supplies  will be counted and reconciled at the site. The study site will be 
required to maintain a log of the temperature  where the study medication is stored. 
 
All medication must be stored in a secure area under the proper storage requirements  with 
access restricted to the site staff pharmacist  or designee(s). 
 
The Investigational medicinal product should not be used for any purpose outside the scope 
of this protocol, nor can Investigational  medicinal  product be transferred or licensed  to any 
party not participating in the clinical study. Data for Investigational medicinal product are 
confidential and proprietary and shall be maintained  as such by the Investigators. 
 
The Principal Investigator  (or an authorized  designee)  must maintain a careful record of the 
inventory of the Investigational medicinal  product received using the Drug Accountability 
Form. The study drug will be destroyed as per MSKCC policy. 


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Page 19 of 45 
 
 
 
 
 
 
 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion  Criteria 
1. Patients must have recurrent or persistent endometrial carcinoma.   Patients with the 
following histologic  epithelial cell types are eligible:  endometrioid  adenocarcinoma, 
serous adenocarcinoma,  undifferentiated  carcinoma,  clear cell adenocarcinoma,  mixed 
epithelial  carcinoma, adenocarcinoma  not otherwise specified  (N.O.S.), mucinous 
adenocarcinoma,  squamous cell carcinoma,  transitional  cell carcinoma,  and 
carcinosarcoma. 
2. Age ≥ 18 years 
3. Patients must have had at least one but no more than four prior chemotherapeutic 
regimens  for management  of endometrial  carcinoma  (including  neo-adjuvant  and/or 
adjuvant chemotherapy).   Initial treatment  may include  chemotherapy,  chemotherapy 
and radiation therapy, and/or consolidation/maintenance  therapy.  Chemotherapy 
administered  in conjunction with primary radiation as a radio-sensitizer  WILL be 
counted as a systemic  chemotherapy regimen. 
4. Patients tumors must have known PI3K pathway activation defined as EITHER of the 
following  on a CLIA-approved molecular  diagnostics  test: 
a. Genomic  alteration resulting in loss of PTEN function including a whole or partial 
gene deletion,  frame shift  mutations,  or non-sense mutations.  Missense mutations  in 
PTEN will not be considered qualifying. 
b. A previously characterized  activating mutation in any component of the pathway 
including:  PIK3CA, AKT1, PIK3R1, PIK3R2, mTOR 
5. Eastern Cooperative Oncology Group (ECOG) performance  status of 0 or 1 
6. Resolution of adverse effects of recent surgery, radiotherapy,  or chemotherapy to Grade 
≤1 prior to first study treatment (with the exception of alopecia or neuropathy). 
7. Patients must have measurable  disease.  Measurable disease is defined by RECIST 
(version 1.1).  Measurable disease is defined as at least one lesion that can be 
accurately measured in at least one dimension (longest  diameter to be recorded).  Each 
lesion must be  10 mm when measured by CT, MRI or caliper measurement  by 
clinical exam; or  20 mm when measured by chest x-ray.  Lymph nodes must be ≥ 15 
mm in short axis when measured by CT or MRI. 
8. No active infection requiring antibiotics  (with the exception of uncomplicated  urinary 
tract infection). 
9. Any other prior therapy directed at the malignant  tumor, including immunologic  agents 
and radiotherapy,  must be discontinued  at least 2 weeks prior to first study treatment. 
10. Adequate hematologic  defined by the following laboratory results obtained within 14 
days prior to first study treatment: 
a. Absolute neutrophil  count (ANC) ≥1500/109dL 
b. Platelet count ≥ 100,000/109dL 


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c. Hemoglobin   ≥ 9.0 g/dL 
11. Adequate hepatic function defined  by the following laboratory results obtained within 
14 days prior to first study treatment: 
a. Total bilirubin≤1.5x the upper limit  of normal (ULN) 
b. AST and ALT ≤ 3.0x ULN (unless the patient has Gilbert’s Syndrome, in which 
case AST and ALT ≤ 5.0x ULN is permitted 
c. Albumin   ≥ 3.5 g/dL 
12. Adequate renal function defined  by the following  laboratory results obtained within 14 
days prior to first study treatment: 
a. Serum creatinine≤1.5x ULN OR creatinine  clearance ≥50 mL/min on the basis of 
the Cockcroft-Gault glomerular  filtration rate estimation 
13. For all patients (regardless of known diabetes) the following is required at screening: 
Fasting blood glucose  ≤ 135 mg/dL (7.49 mmol/L)  and HbA1c   ≤7.0% 
14. For patients of childbearing  potential,  agreement  to use two effective  forms of 
contraception (e.g., surgical sterilization,  a reliable  barrier method, birth control pills, or 
contraceptive  hormone implants)  and to continue  its use for the duration of the study 
and for 30 days after the last LY3023414 dose. 
15. Patients must have been enrolled,  or agree to consent to the companion genomic 
profiling study MSKCC IRB# 12-245. 
16. Willingness  to sign written informed  consent to this study. 
 
6.2 
Subject Exclusion  Criteria 
 
1. Patients with known concurrent activating RAS/RAF mutation  or loss of function 
mutation or deletion in NF1 of NF2 resulting in MAP kinase pathway activation. 
Patients are not required to be evaluated for these alterations  if not already performed. 
2. Patients with diabetes requiring insulin  or requiring more than one non-insulin 
hypoglycemia  agents. 
3. Patients previously treated with an mTOR, AKT, or PI3K inhibitor  (including but not 
limited  to GDC-0941, GDC-0980, BEZ235, BKM120, LY294002, PIK-75, TGX-221, 
XL147, XL765, SF1126, PX-866, D-87503, D-106669, GSK615, CAL101, everolimus, 
temsirolimus,  and ridaforolimus).  For agents not listed, the Study PI or Co-PI will make 
a determination. 
4. History of myocardial infarction or unstable angina  within 6 months prior to first  study 
treatment. 
5. New York Heart Association Class II or greater congestive  heart failure. 
6. Patients with a QTcF interval  of >450 msec on screening electrocardiogram  (ECG) 
Note: If >450 msec on the first ECG, 2 additional ECGs can be ordered same day 
and then the average may be used to determine  eligibility. 
7. History of malabsorption syndrome or other condition that would interfere  with enteral 
absorption. 
8. Inability or unwillingness  to swallow pills 
9. Clinically significant  history of liver  disease, including cirrhosis  and current alcohol 
abuse. 


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10. Active hepatitis B or hepatitis C infection. Patients with previously  resolved hepatitis B 
infection are eligible. Presence of positive test results for hepatitis B infection who have 
resolved the infection (defined by being positive for HB surface antibody (anti-HBs) and 
polymerase chain reaction (PCR) assay is negative for HBV DNA) are eligible. Patients 
positive  for HCV antibody are eligible  only if testing for HCV RNA is negative. 
11. Known HIV infection. 
12. Need for current chronic corticosteroid  therapy (≥ 10 mg of prednisone per day or an 
equivalent  dose of other anti-inflammatory corticosteroids) 
13. Pregnancy,  lactation,  or breastfeeding 
14. Current severe, uncontrolled  systemic  disease (e.g., clinically significant 
cardiovascular,  pulmonary,  or metabolic  disease) 
15. Major surgical procedure or significant  traumatic  injury  within 28 days prior to Day 1 or 
anticipation of the need for major surgery during the course of study treatment. 
16. Known untreated or active central nervous system (CNS) metastases (progressing or 
requiring anticonvulsants  or corticosteroids  for symptomatic  control).   Patients with a 
history of treated CNS metastases are eligible,  provided that they meet all of the 
following criteria: 
a. Presence of measurable  disease outside the CNS 
b. No radiographic  evidence of worsening upon the completion of CNS-directed 
therapy and no evidence of interim  progression between the completion of 
CNS-directed therapy and the screening radiographic  study 
c. No history of intracranial hemorrhage  or spinal cord hemorrhage 
d. No ongoing requirement  for dexamethasone  as therapy for CNS disease 
(anticonvulsants  at a stable dose are allowed) 
e. Absence of leptomeningeal disease 
17. Inability to comply with study and follow-up  procedures. 
18. Any other disease, metabolic  dysfunction,  physical examination finding,  or clinical 
laboratory finding that, in the investigator’s  opinion,  gives reasonable suspicion of a 
disease or condition that contraindicates  the use of an investigational drug or that may 
affect the interpretation of the results or render the patient at high risk from treatment 
complications. 
 
 
7.1 
RECRUITMENT PLAN 
 
Potential research subjects willl      be identified  by a member of the patient’s treatment team, the 
protocol investigator  or research team within the Gynecologic  Medical Oncology Group at 
Memorial Sloan-Kettering Cancer Center (MSKCC). Patient recruitment  will  occur in the 
Gynecologic  Medical Oncology clinics  at MSKCC. The investigator  will discuss the study with 
suitable  participants,  and should the patient consent to proceed with protocol therapy, will enroll 
their patient’s in the research study. Based on historical accrual rates in similar  populations,  we 
anticipated  successful enrollment  of 2 patients per month yielding a total accrual time of 12 
months.  However, due to a slower than expected accrual rate, we have expanded the eligibility to 
allow patients who have received up to 4 prior lines of therapy to be eligible.  We believe  that with 
this modification,  we will be able to accrue approximately 2 patients per month onto this study. 
 
 
Patients must have PI3K pathway activation defined  as EITHER of the following: 


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Page 22 of 45 
 
 
 
 
 
 
 
1. Genomic  alteration resulting in loss of PTEN function including a) whole or partial gene 
deletion,  frame shift mutations,  or non-sense mutations.  Missence mutations  in PTEN will 
not be considered qualifying. 
2. A previously characterized  activating mutation  in any component of the pathway including: 
PIK3CA, AKT1, PIK3R1, PIK3R2, mTOR 
 
Patients must also not have a known concurrent activating RAS/RAF mutation  or loss of function 
alternation in NF1 of NF2 resulting in MAP kinase pathway activation. 
 
Any mutational profiling performed in a CLIA laboratory either as routine  standard of care or as 
part of a dedicated genomic  profiling study such as MSKCC IRB# 12-245 will be accepted. For 
patients who have not had mutational  profiling performed in a CLIA laboratory or as part of a 
prior genomic  profiling study, formally consenting to MSKCC IRB# 12-245 Part A will be 
required before consenting to the current study to ensure that the consenting patient has a  PI3K 
pathway activating mutation as detailed above. 
 
Patients who respond to therapy and then progress will be offered  a consent to MSKCC IRB# 12- 
245 Part B in order to obtain post-progression material for molecular  profiling in order to 
determine  the mechanism(s)  underlying acquired resistance.  Participation in this companion study 
is optional for enrolled patients.  IRB# 12-245 Part B is a separate consent, but it is similar  to IRB# 
12-245 Part A. IRB# 12-245 Part B consent  is specifically utilized  in cases where patients have 
received experimental  targeted therapy and are undergoing repeat mutation profiling of post- 
treatment malignancy in an effort to determine  the mechanism(s)  underlying acquired resistance. 
Specifically,  we will be looking for presence of genetic alterations  which based on their 
understood biological mechanism may explain acquired resistance (for example, second “hits” on 
the PI3K pathway). 
 
 
8.1 
PRETREATMENT EVALUATION 
 
Within 28 days prior to tre atme nt start: 
• History and Physical examination 
• Review of concomitant  medications 
• Vital signs (blood pressure, heart rate and temperature),  weight  and height 
• Performance  status 
• Toxicity assessment 
• 12-lead ECG 
• Radiographic  tumor measurements  (CT C/A/P, MRI, Chest X-ray) 
• Hepatitis  B and C screening 
• Request archival tumor tissue (if required and done through IRB 12-245) 
 
 
 
Within 7 days prior to tre atme nt start: 
• Complete Blood Count (CBC) with differential  and platelets 


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• Comprehensive  profile  (BUN, creatinine  (or creatinine  clearance), sodium, 
potassium,  chloride, CO2, calcium,  toral bilirubin,  total protein, albumin,  alkaline 
phosphatase, AST, ALT) 
• Phosphorus 
• Magnesium 
• PT/PTT 
• 
CA125 
• Hemoglobin A1c 
• Insulin Level 
• Fasting blood glucose 
• Body weight 
• Urinalysis 
• Pregnancy test (in women of child bearing potential) 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 Treatment 
 
LY3023414 200 mg will be dosed orally twice a day. Each cycle will be 21 days in 
duration.   Patients will receive study treatment  until disease progression,  intolerable  
toxicity,  elective  withdrawal from the study, study completion,  or study termination.  In 
limited  circumstances  patients may be treated beyond progression if, in the opinion of the 
Principal Investigator,  the patient is benefiting from treatment.  Approval from Eli Lilly will 
be required in these circumstances. 
 
LY3023414 should be taken approximately 12 hours apart. Patients should not consume 
food for approximately 1 hour before taking the dose of LY3023414. If a dose is vomited 
within one hour of ingestion,  it will be replaced. If vomiting occurs more than 1 hour after 
dosing, it will be considered a complete dose and will not be replaced. 
 
Concomitant  medication  and treatment 
 
Concomitant  medication is defined  as any prescription  or over-the-counter  preparation, 
including vitamins  and supplements.  Patients may continue  their baseline  medication(s). 
All concomitant  medication(s)  must be recorded. Any diagnostic,  therapeutic  or surgical 
procedure performed  during the study period should  be recorded, including  dates, 
description  of the procedure(s) and any clinical  findings. 
 
LY3023414 is a weak inhibitor  of cytochrome P450 3A4 (CYP3A4) in patients and 
thereby impacts (decreases) the metabolic  clearance of drugs that are metabolized  through 
CYP3A4 (See also IB Section 6.1.2). The clinical implications  of this risk have yet to be 
determined.   Patients should avoid taking concomitant  medications  that are CYP3A4 
substrates (for example,  midazolam). 
 
Investigators  should  monitor patients  for unexpected clinical adverse effects as a result of 
unexpected high exposure to LY3023414 due to any potential interaction of concomitant 
medicat ions  with LY3023414. 


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9.3 Correlative Studies 
Cell Free DNA: 2 extra Streck BCT tubes will be collected at the time of routine blood collection 
at the specified  time points in the calendar in Section 10.0. Processing will occur per MSKCC 
laboratory medicine  procedures. 
 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
 
PARAMETER 
Screening 
Cycle 1 
Cycle 2+ 
End of 
Treatment 
Follow-up 
Day 
28 days 
before 
start 
7 Days 
before 
start 
1 
8 
±3 days 
15 
±3 
days 
1 
±4 days 
30 days 
±14 days 
Every 3 
months 
until death 
±1 month 
Medical History 
X 
Physician 
Examination 
X 
X 
X 
X 
X 
X 
Performance 
Status 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
Vital  Signs (blood 
pressure, heart 
rate and 
temperature) 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
CBC,  differential, 
hemoglobin, 
platelets, 
Electrolytes, 
BUN,  Creatinine, 
Ca, Mg, 
Phosphorus, 
Bilirubin, 
AST/SGOT, 
ALT/SGPT, 
Alkaline 
Phosphatase 
X 
X2 
X 
X 
X 
X 
Fasting  (≥8 
hours) Blood 
Glucose 
X 
X2 
X 
X 
X 
X 
Insulin Level 
X 
X2 
X 
X 
X 
X 
Hemoglobin  A1c 
X 
X2 
X 
X 


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PARAMETER 
Screening 
Cycle 1 
Cycle 2+ 
End of 
Treatment 
Follow-up 
Day 
28 days 
before 
start 
7 Days 
before 
start 
1 
8 
±3 days 
15 
±3 
days 
1 
±4 days 
30 days 
±14 days 
Every 3 
months 
until death 
±1 month 
PT, INR,  PTT 
X 
X 
Pregnancy test 
X1 
X 
CA125 
X 
X2 
X 
X 
Electrocardiogra 
m 
X 
X 
X 
X 
CELL-Free   DNA 
X 
X 
X (Odd 
cycles 
Day1 
only) 
Radiographic 
disease 
assessment 
X 
X3 
X4 
X4 
Patient drug diary 
X 
Survival Follow- 
up 
X5 
1. 
If the patient is of child-bearing  potential per MSKCC  guidelines. Must be obtained within  72 hours prior to 
initiating  protocoltherapy. 
2. 
Study can be omitted on Cycle 1 Day 1 with screen labs performed  within  72 hours. 
3. 
Performed  during week 3 of each even numbered cycle (Days 15-21). 
4. 
Only if patient discontinues for reasons other than progression, repeated every 3 months +/ -2 weeks until disease 
progression or initiation  of alternative anti-cancer therapy. 
5. 
Phone call every 3 months. 
 
 
11.1 
TOXICITIES/SIDE EFFECTS 
 
The dose delay and reduction instructions  provided in Tables 11A and 11B are intended to 
serve as guidelines  to allow ongoing treatment  for patients experiencing clinical  benefit 
without  signs or symptoms  of progression while  ensuring patient safety. 
Patients may 
temporarily suspend dosing of LY3023414 for up to 14 days if they experience  toxicity that 
is considered related to LY3023414 and requires that a dose be held. Patients who miss ≥ 
14 consecutive  days of scheduled LY3023414 treatment because of LY3023414 related 
AEs will be discontinued  from the study. LY3023414 dosing delay beyond 2 weeks and up 
to 28 days may be permissible,  if AEs are not considered to be primarily related to 
LY3023414 and the investigator  deems continuation to have clinical  benefit  for the patient. 
Exceptions  may be made after discussion with the approval by the Principal Investigator. 
Patients may suspend dosing of study drug for radiation therapy or surgery that is 
considered by the treating physicians  to be of clinical benefit  for the patient. After 
completion of the intervention,  patients may restart the study drug as long as all criteria for 
dosing are met and there is no evidence of disease progression  (unless approved by PI and 
sponsor as noted previously). 


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Dose modifications  for LY3023414 for select AEs, should follow  the guidance  provided in 
Table 11A, and required dose reductions should follow  the dose levels outlined  in Table 
11B.  No dose re-escalation will be allowed. 
Table 11A: Dose Delay Guidelines for LY3023414-Related Adverse Events 
Event Type 
Grade and Frequency 
Dosing 
Hyperkalemia 
Grade 2 (baseline potassium ≤ULN) 
Grade 2 (baseline potassium Grade 
1) 
Grade 3: first and second event 
Grade 3: third event 
Grade 4 
• 
Hold until Grade ≤1 
• 
Restart at same dose if 
recovery to Grade ≤1 is ≤7 
days. 
• 
Restart at next lower dose if 
recovery to Grade ≤1 is ≥7 
days 
• 
Consider holding  until Grade 
≤1 taking into account 
change from baseline. 
• 
Otherwise, follow  directions 
above 
• 
Hold until Grade ≤1 
• 
Restart at next lower dose 
• 
Discontinue 
• 
Discontinue 
Hyperglycemia 
Grade 3, asymptomatic a 
Grade 3, with symptoms a 
Grade 3, with severe symptoms b, 
or requiring hospitalization,  or 
Grade 4 (non-life-threatening) 
Grade 4, life-threatening 
• 
Begin home monitoring  and 
check at next visit; if 
persistent pre-dose values of 
Grade 3, start or adjust oral 
anti-hyperglycemic  agent or 
reduce by one dose level. 
• 
Hold until resolution of 
symptoms and Grade ≤2. 
• 
Consider starting or adjusting 
oral anti-hyperglycemic  
agent or restarting at next 
lower dose level. 
• 
Hold until resolution of 
symptoms and Grade ≤2. 
• 
Start or adjust oral anti- 
hyperglycemic  agent. Restart 
at next lower dose level. 
• 
Discontinue 
Anemia 
Grade 1-2 
Grade 3: first event 
Grade 3 (second event) or Grade 4 
(non-life-threatening) 
Grade 4 (life threatening) 
• 
Maintain dose level and 
initiative  standard supportive 
care 
• 
Hold until Grade ≤1 
• 
Consider restarting at next 
lower dose 
• 
Hold until Grade ≤1 
• 
Restart at next lower dose 
• 
Discontinue 


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IRB Number: 15-079 A(12) 
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Thrombocytopenia 
Grade 1 
• 
Maintain dose level and 
initiative  standard supportive 
care 
Grade 2-3 
• 
Hold until Grade ≤1 
• 
Restart at next lower dose 
Grade 4 
• 
Discontinue 
Other Clinically 
Significant  Drug- 
Related AE 
Grade 1 
• 
Maintain dose level and 
initiative  standard supportive 
care 
Grade 2 (intolerable) 
• 
Consider holding  until Grade 
≤1 and  restarting at next 
lower dose 
Grade 3-4 
• 
Hold until Grade ≤1 
• 
Restart at next lower dose 
Grade 4 (life-threatening) 
• 
Discontinue 
Rash 
Grade 1-2 
Grade 3: First Event 
Grade 3: Recurrent 
• 
Maintain dose level and 
initiative  standard supportive 
care 
• 
Hold Until ≤ Grade 1 and 
restart at same dose. 
• 
Initiative  standard supportive 
care an 
• 
Dermatology  Consultation 
• 
Hold Until ≤ Grade 1 and 
restart at next lower dose. 
• 
Initiative  standard supportive 
care an 
• 
Dermatology  Consultation 
ULN = upper limit  of normal. Adverse event grading is based on the current version of the National Cancer 
Institute Common  Terminology  Criteria  for Adverse Events. 
a Symptoms  of hyperglycemia  include blurry vision, polydipsia, and polyuria. 
b Severe symptoms of hyperglycemia  include neurological symptoms (lethargy, focal signs, or 
obtundation), hyperventilation, abdominal pain,  and hypotension. 
Table 11B: LY3023414 Dose Reduction Schedule 
Starting Dose 
200mg twice daily 
Dose Level -1 
150mg twice daily 
Dose Level -2 
100mg twice daily 
Dose Level -3 
Discontinue 
 
It is expected that patients with nausea, emesis, diarrhea, or constipation will receive 
appropriate medical management  without  dose modification.  However, patients with 


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Page 28 of 45 
 
 
 
 
 
persistent (≥ 24 hours) Grade≥3 toxicity  in spite of optimal medical management  require 
reduction of one dose level and delay in subsequent  therapy for a maximum of 2 weeks 
until recovered to Grade 1. 
Other non-hematologic toxicities with an impact on organ function of Grade ≥ 2 require 
reduction of one dose level and delay in subsequent therapy for a maximum of 28 days 
until recovered to Grade 1, or pre-therapy baseline 
 
Hematopoietic Growth Factors and Blood Products 
 
Erythropoietin,  darbepoetin alfa, romiplostim and/or hematopoietic  colony-stimulating 
factors for treatment  of cytopenias should be administered  according to institutional 
guidelines.  Transfusion thresholds  for blood product support will be in accordance with 
institutional guidelines. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Antitumor Effect – Solid Tumors 
Response and progression will be evaluated  in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline  (version 1.1) [22]. Changes in the largest diameter (unidimensional 
measurement)  of the tumor lesions and the shortest diameter in the case of malignant 
lymph nodes are used in the RECIST criteria. 
 
12.1 Definitions 
 
Evaluable  for toxicity.  All patients will be evaluable  for toxicity from the time of their first 
treatment on study. 
 
Evaluable  for objective response. Only those patients who have measurable  disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable  for response. These patients will have their response 
classified  according to the definitions  stated below. (Note: Patients who exhibit  objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable  Non-Target Disease Response. Patients who have lesions  present at baseline that 
are evaluable  but do not meet the definitions  of measurable  disease, have received at least 
one cycle of therapy, and have had their disease reevaluated  will be considered evaluable 
for non-target disease. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
 
 
 
 
 
12.2 Disease Parameters 


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Measurable  disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest  diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor 
measurements  must be recorded in millimeters  (or decimal fractions  of centimeters). 
 
Note: Tumor lesions  that are situated in a previously irradiated area will not be considered 
measurable  unless progression is documented  or a biopsy is obtained to confirm persistence 
at least 90 days following completion of radiation therapy. 
 
Malignant  lymph nodes. To be considered pathologically enlarged and measurable,  a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness  recommended to be no greater than 5 mm). At baseline  and in follow-up,  only the 
short axis will be measured and followed. 
 
Non-measurable  disease. All other lesions  (or sites of disease), including small lesions 
(longest  diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable  disease. Bone lesions,  leptomeningeal disease, ascites, 
pleural/pericardial effusions,  lymphangitis  cutis/pulmonitis,  inflammatory breast disease, 
and abdominal masses (not followed  by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions  that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant  lesions  (neither  measurable nor non-measurable)  since they 
are, by definition,  simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- 
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions. All measurable  lesions up to a maximum  of 2 lesions per organ and 5 
lesions in total, representative  of all involved  organs, should be identified  as target lesions 
and recorded and measured at baseline.  Target lesions  should be selected on the basis of 
their size (lesions  with the longest diameter),  be representative  of all involved  organs, but 
in addition should be those that lend themselves  to reproducible  repeated measurements.  It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement  in which circumstance  the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters  (longest for non-nodal lesions, 
short axis for nodal lesions)  for all target lesions will be calculated  and reported as the 
baseline sum diameters. If lymph nodes are to be included  in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize  any objective  tumor regression in the measurable  dimension of the disease. 
 
Non-target lesions.  All other lesions  (or sites of disease) including any measurable  lesions 
over and above the 5 target lesions should be identified  as non-target lesions and should 
also be recorded at baseline.  Measurements  of these lesions  are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout  follow-up. 


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12.3 Methods for Evaluation of Measurable Disease 
 
All measurements  should  be taken and recorded in metric notation using a ruler or calipers. 
All baseline  evaluations  should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. The same 
method of assessment and the same technique  should be used to characterize  each  
identified  and reported lesion at baseline and during followup.  Imaging-based  evaluation is 
preferred to evaluation by clinical  examination unless the lesion(s)  being followed  cannot 
be imaged but are assessable by clinical exam. 
 
Clinical  lesions: Clinical lesions  will only be considered measurable when they are 
superficial  (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions,  documentation by color 
photography,  including a ruler to estimate  the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions  when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline  has defined measurability of lesions  on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness  greater than 5 mm, the minimum  size for a measurable  lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations  (e.g. for body scans), but NOT 
lung. 
 
Use of MRI remains  a complex issue. MRI has excellent  contrast, spatial, and temporal 
resolution;  however,  there are many image acquisition variables  involved  in MRI, which 
greatly impact image quality,  lesion conspicuity,  and measurement.  Furthermore,  the 
availability of MRI is variable  globally.  As with CT, if an MRI is performed, the technical 
specifications  of the scanning sequences used should be optimized  for the evaluation of the 
type and site of disease. Furthermore,  as with CT, the modality used at follow-up  should be 
the same as was used at baseline and the lesions should be measured/assessed  on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines  to prescribe specific  MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally,  the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques,  if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET- 
CT is not always of optimal diagnostic  CT quality for use with RECIST measurements. 
PET-CT scans are not always done with oral and IV contrast. In addition, the PET portion 
of the CT introduces  additional data which may bias an investigator  if it is not routinely or 
serially performed. For these reasons, the GOG will not allow PET-CT use for RECIST 1.1 
response criteria. 
 
Ultrasound:  Ultrasound  is not useful in assessment  of lesion size and should not be used as 
a method of measurement.  Ultrasound  examinations  cannot be reproduced in their entirety 
for independent  review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique  and measurements  will be taken from one 


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assessment to the next. If new lesions  are identified  by ultrasound  in the course of the 
study, confirmation by CT or MRIs advised. If there is concern about radiation exposure at 
CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques  for objective tumor 
evaluation is not advised. However, such techniques  may be useful to confirm complete 
pathological response when biopsies are obtained or to determine  relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
CA125 (Ovarian, fallopian tube and primary peritoneal cancer trials): CA125 alone cannot 
be used to assess response. If CA125 is initially above the upper normal limit,  it must 
normalize  for a patient to be considered in complete clinical response. Specific  guidelines 
for CA-125 response (in recurrent ovarian cancer) have been published  (23) In addition; 
the Gynecologic  Cancer Intergroup has developed CA-125 progression criteria which are 
to be integrated  with objective tumor assessment for use in first-line  trials in ovarian cancer 
(24). 
 
Cytology,  Histology: These techniques  can be used to differentiate  between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effus ion that appears or 
worsens during treatment  when the measurable  tumor has met criteria  for response or 
stable disease is mandatory to differentiate  between response or stable disease (an effusion 
may be a side effect of the treatment)  and progressive  disease. 
 
FDG-PET: While FDG-PET response assessments  need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement  CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified  according to the following algorithm: 
 
a. Negative FDG-PET at baseline,  with a positive  FDG-PET at follow-up  is a sign of PD 
based on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive  FDG- 
PET at follow-up  corresponds to a new site of disease confirmed  by CT, this is PD. If the 
positive  FDG-PET at follow-up  is not confirmed  as a new site of disease on CT, additional 
follow-up  CT scans are needed to determine  if there is truly progression occurring at that 
site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the 
positive  FDG-PET at follow-up  corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images,  this is not PD. 
 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar  to a biopsy in 
cases where a residual radiographic  abnormality is thought  to represent fibrosis  or scarring. 
The use of FDG-PET in this circumstance  should be prospectively described in the protocol 
and supported by disease-specific  medical literature  for the indication.  However, it        
must be acknowledged  that both approaches may lead to false positive  CR due to  
limitations  of FDG-PET and biopsy resolution/sensitivity. 


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Note: A ‘positive’  FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.4 Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters  of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive  Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest  sum on study (this includes  the baseline  sum if that 
is the smallest  on study). In addition to the relative  increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient  shrinkage  to qualify for PR nor sufficient  increase 
to qualify for PD, taking as reference the smallest  sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions  and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short 
axis). Note: If CA125 is initially above the upper normal limit,  it must normalize  for a 
patient to be considered in complete clinical  response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)  and/or maintenance  of 
CA125 level above the normal limits. 
 
Progressive  Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal  progression should not normally 
trump target lesion status. It must be representative  of overall disease status change, not a 
single  lesion increase 
. 
 
Although a clear progression of “non-target” lesions only is exceptional,  the opinion of the 
treating physician should prevail in such circumstances,  and the progression status should 
be confirmed  at a later time by the review panel (or Principal Investigator). 
 
 
Progression Based on Serum CA-125 (for randomized  phase 3 trials of initial therapy 
of ovarian, fallopian tube and primary  peritoneal cancer ONLY): 


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Progression can be based upon serum CA-125, only during the period following 
completion of cytotoxic  chemotherapy,  if one of the three conditions  is met: 
 
1. Patients with elevated CA-125 pretreatment  and normalization of CA-125 must show 
evidence of CA-125 greater than or equal to two times the upper normal limit  on two 
occasions at least one week apart 
 
OR 
 
2. Patients with elevated CA-125 pretreatment,  which never normalizes  must show 
evidence of CA-125 greater than or equal to two times the nadir value on two occasions at 
least one week apart 
 
OR 
 
3. Patients with CA-125 in the normal range pretreatment  must show evidence of CA-125 
greater than or equal to two times the upper normal limit  on two occasions at least one 
week apart. When disease progression is defined by CA-125 criteria  alone, imaging using 
the same modality and encompassing the same field as in the initial  pretreatment  evaluation 
should be obtained within 2 weeks that such progression is documented. 
 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment  until 
disease progression/recurrence  (taking as reference for progressive  disease the smallest 
measurements  recorded since the treatment started). The patient's best response assignment 
will depend on the achievement  of both measurement  and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation  is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented  at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript  for further  details on what is evidence of a new lesion. 
** 
Only for non-randomized  trials with response as primary endpoint. 
*** 
In exceptional circumstances,  unequivocal progression in non-target lesions may be 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal  PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly  used as an endpoint for assessment of efficacy  in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement  criteria  are met for CR or PR (whichever  is first recorded) until the first date 
that recurrent or progressive  disease is objectively documented (taking as reference for 
progressive  disease the smallest  measurements  recorded since the treatment  started). The 
duration of overall CR is measured from the time measurement  criteria are first met for CR 
until the first date that progressive  disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest  measurements  recorded 
since the treatment  started, including the baseline measurements. 
 
Progression-Free Survival 
Progression-Free Survival  (PFS) is defined as the duration of time from start of treatment 
to time of recurrence,  progression,  or death, whichever  occurs first. 
 
 
Survival 
Survival is defined as the duration of time from start of treatment to time of death or the 
date of last contact 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients may withdraw  from the study at any time.  Any patient who withdraws will be 
encouraged to return to the study center for a treatment  completion visit.  Patients who 
accepted as disease progression. 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without  objective  evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 


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discontinue  early should return within 30 days following the final dose of study treatment. 
The primary reason for discontinuation must be recorded in the medical record. 
 
Patients may be withdrawn from the study if they experience any of the following: 
• Disease progression,  per investigator  assessment 
• Intolerable  toxicity of LY3023414 
 
Other reasons for patient discontinuation may include,  but are not limited  to, the following: 
• Change in patient eligibility 
• Non-compliance 
• Patient decision 
• If the patient becomes pregnant 
• If patient requires more then 2 dose reductions of LY3023414 
• If treatment is delayed for more than 28 consecutive  days 
 
The investigator  has the right  to discontinue  a patient from the study for any medical 
condition that the investigator  determines  may jeopardize the patient’s safety if he or she 
continues  in the study; for reasons of noncompliance  (e.g., missed doses, visits);  or if the 
investigator  determines  it is in the best interest of the patient. 
 
 
14.1 
BIOSTATISTICS 
 
This study aims to assess the activity of LY3023414 in patients with PI3K-pathway activated 
recurrent or persistent endometrial  cancer as measured by the best overall response rate as 
determined  by RECIST 1.1. Assuming we use a binary endpoint of response, defined as best 
overall response of CR or PR versus not, a sample size of 25 patients provides 90% power to test 
the hypothesis  that the response rate is promising (defined  as 30% or higher)  against a non- 
promising rate of 10% or lower. This calculation  is based on historical  data from studies with 
ineffective  agents in a similar  patient population,  which have ORR < 10% and PFS rate at 6 
months < 20% (Fracasso et al, 2006, Schilder et al. 2004, Garcia et al. 2008 Aghajanian et al, 
2011), and uses an exact, one-sample test for binomial  proportion, with Type I error=10%. At the 
end of the study, if at least 5/25 responses are observed then this will be considered a positive 
study (i.e. conclude that RR is >10%). 
 
Based on historical  accrual rates in similar  populations,  and with the increased prior lines  of 
therapy that will not be allowed for eligibility,  we anticipate  successful enrollment  of 2 patients per 
month yielding a total accrual time of 12 months.  Accrual will continue  until 25 evaluable  for 
response patients are treated (evaluable  patients are defined in section 12.1) 
 
 
In addition we will report the following statistics: 
1. The clinical benefit rate (CBR) of LY3023414 therapy, defined as the percentage of 
patients with complete response (CR) + partial response (PR) + stable disease (SD) ≥12 


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weeks from the start of treatment will be reported and the 90% confidence  interval will 
be estimated using exact binomial  proportions 
2. Progression  free survival (PFS), defined as the duration of time from start of treatment 
to time of recurrence,  progression, or death due to any cause, whichever  occurs first. 
Patients will be censored at last follow  up date. The Kaplan Meier estimate  of median 
PFS will be reported. 
3. Overall survival  (OS), defined  as the duration of time from start of treatment until the 
date of death due to any cause. Patients will be censored at last follow  up date. The 
Kaplan Meier estimate  of median OS will be reported. 
4. Tthe duration of response (DOR) of LY3023414 therapy, defined as the time from 
which measurement  criteria  are met for CR or PR (whichever  status is recorded first) 
until the first date of documented disease progression,  will be estimated using the 
Kaplan Meier method. Patients without  documented progression will be censored at last 
follow  up. 
5. Adverse events by the current version of Common Terminology Criteria for Adverse 
Events version 4 (CTCAE v4.0) will be tabulated in order to assess the safety profile 
and tolerability of LY3023414 therapy in patients with PI3K activated 
recurrent/persistent  endometrial cancer. 
In addition the study will analyze  the following variables as part of assessing exploratory aims 
in a subset of patients who consent to 12-245: 
1. For patients who have not already had their tumors molecularly profiled using the 
MSK-IMPACT platform,  pretreatment  archival tumor tissue will be obtained for this 
purpose. Genomic alterations  defined by MSK-IMPACT testing performed on this 
pretreatment  archival tumor tissue will be correlated to objective responses outcomes in 
an exploratory manner.  Consent for this testing,  to be performed in the CLIA  
laboratory, will be obtained through a companion study MSKCC IRB# 12-245. 
Genomic  alterations  will be binary and Fisher's exact test will be used to assess the 
correlation between genomic  alterations  and response (binary). 
 
2. Serial pre-, on- and post-treatment blood samples will be collected for cell-free tumor 
DNA analysis  and sequenced using continuous  quantitative  methods (digital droplet 
PCR or hybridization capture next-generation  sequencing)  for the PI3K- pathway 
alterations  identified  by pre-treatment archival tumor testing and descriptively 
correlated to clinical  outcome. Pre and post treatment samples will be assessed 
graphically  and pre treatment archival tumor testing will be assessed graphically with 
clinical outcome. 
 
3. Patients who respond to therapy and then progress will be offered optional consent to 
MSKCC IRB# 12-245 Part B in order to obtain post-progression material for molecular 
profiling in order to determine  the mechanism(s)  underlying acquired resistance. 
A subset analysis  of patients who progress and have post progression material for 
molecular  profiling will be performed in order to determine  the mechanism(s) 
underlying acquired resistance.  Specifically,  we will be looking for presence of genetic 
alterations  which based on their understood biological  mechanism  may explain 
acquired resistance (for example, second “hits” on the PI3K pathway). 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 


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15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled  Criteria for Patient/Subject  Eligibility. 
 
Obtain informed  consent, by following procedures defined in section entitled  Informed 
Consent Procedures. 
During the registration process registering individuals  will be required to complete a 
protocol specific  Eligibility Checklist. 
All participants  must be registered through the Protocol Participant  Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available  Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations  must be submitted  via the 
PPR Electronic  Registration System (http://ppr/).   The completed signature  page of the 
written consent/RA  or verbal script/RA,  a completed Eligibility Checklist  and other 
relevant  documents must be uploaded via the PPR Electronic  Registration System. 
15.2 
Randomization 
 
NA 
 
 
 
16.0 
DATA  MANAGEMENTISSUES 
 
A research study assistant (RSA) will be assigned to study. The responsibilities  of the RSA 
include  project compliance,  data collection,  extraction and data entry, data reporting, 
coordination of the activities  of the protocol study team and, and of the flow of regulatory 
paperwork. 
The data collected for the study will be entered into a secure database (CRDB). All routine 
blood test results required per the protocol will be captured in CRDB in addition to 
baseline medical conditions  and disease informatio n,  response assessments, off-study 
documentation,  and toxicity grade and attribution.  Source documentation will be available 
to support the computerized  patient record. 
MSKCC will hold the IND and will be responsible for all safety monitoring. All SAEs will 
be reported to the MSKCC IRB. The safety of the study will be monitored by the MSKCC 
Data and Safety Monitoring Committee. 
Weekly registration reports will be generated by the RSA and reviewed by the PI to 
monitor  patient accruals and completeness  of registration data. Routine  data quality reports 
will be generated to assess missing data and inconsistencies. 
Accrual rates and extent and accuracy of evaluations  and follow  up will be monitored 
periodically throughout  the study. Recurrent lapses in data collection,  deviations  or 


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violations will be discussed with the study team and a corrective plan will be generated. 
Accrual goals and factors impacting accrual goals will be discussed at the weekly New 
Patient/Protocol meetings. 
 
16.1 
Quality Assurance 
 
The data and safety monitoring plan at Memorial Sloan-Kettering Cancer Center was 
approved by the National Cancer Institute  in September 2001. The plan addressed the new 
policies  set forth by the NCI and the document entitled  "Policy of the National Cancer 
Institute  for data and safety monitoring of clinical  trials" which can be found at 
http://grants.nih.gov/grants/guide/notice- files/not98-084.html.  The DSM plans at MSKCC 
were established  and are monitored  by the Office of Clinical Research. The MSKCC data 
and safety monitoring plan can be found on the MSKCC Internet at 
http://inside2/clinresearch/Documents/MSKCC  Data and Safety Monitoring Plans.pdf. 
There are several different  mechanisms  by which clinical  trials are monitored  for data, 
safety and quality.   There are institutional processes in place for quality assurance (e.g., 
protocol monitoring,  compliance  and data verification audits, therapeutic  response, and 
staff education on clinical  research QA) and departmental procedures for quality 
control, plus there are two institutional committees  that are responsible  for monitoring the 
activities  of our clinical  trials programs. Memorial Sloan-Kettering Cancer Center has set 
up three distinct  monitoring processes for our clinical  trials program. There are two sub- 
committees  that have the responsibility of data and safety monitoring.  These are joint sub- 
committees  with dual-reporting responsibilities.  The Data and Safety Monitoring 
Committee  (DSMC) is the sub-committee  responsible for monitoring all Phase 1, 2, 1/2, 
pilot and non-phase clinical trials. The Data and Safety Monitoring Board (DSMB) is the 
sub-committee  responsible  for monitoring Phase 3 randomized  clinical  trials. The 
Therapeutic  Response Review Committee  (TRRC) is the sub- committee  of Research 
Council responsible  for the independent  therapeutic  response review for participants  in 
IRB/PB approved clinical trials where therapeutic  efficacy is a stated primary  objective; 
typically phase 2 and 3 trials. Formal monitoring of such studies is designed to ensure that 
the interests of the participants  are being scrutinized  on a regular basis, and that the trial is 
progressing in a satisfactory manner. 
The Data and Safety Monitoring Committee  (DSMC) convenes once per quarter and 
monitors  the risk participants  are exposed to, the progress of the study, the adequacy of the 
data storage and whether sufficient  data are being entered into the CRDB. The DSMC 
monitors  phase 1, 2, 1/2, pilot and non-phase trials that are not being monitored by an 
industrial sponsor, and which meet the NCI definition of a Clinical Trial. This trial will 
qualify for monitoring by the DSMC. 
During the protocol development  and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required, and the monitoring procedures will be 


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Page 39 of 45 
 
 
 
 
 
established  at the time of protocol activation.  A detailed description of the data to be 
collected, process of data collection (i.e., data manager  and/or data management  office), 
database that will be utilized  for data collection and storage (e.g., Clinical Research 
Database (CRDB), user-supported software), reporting requirements  of the data to the 
institution (IRB), the sponsor and/or governing  agency. 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute  in September 2001.  The plans address the 
new policies set forth by the NCI in the document entitled  “Policy of the National Cancer 
Institute  for Data and Safety Monitoring of Clinical Trials” which can be found 
at:  http://www.cancer.gov /clinicaltrials/conducting/dsm-guidelines/pag e1.  The DSM Plans 
at MSKCC were established  and are monitored  by the Office of Clinical  Research.  The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://smsk psps9/dept/ocr/OCR%20Website%20Documents/Clinical%20 Research %20Qua  
lity%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Pl   
an.pdf 


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17.1 
PROTECTION OF HUMAN SUBJECTS 
 
 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may a lllow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure  of 
protected health information will be limited  to the individuals  described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator  and approved by the IRB and Privacy Board (IRB/PB). 
17.2 
Serious Adverse Event(SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient  hospitalization or prolongation of existing 
hospitalization 
• A persistent or significant  incapacity or substantial disruption of the ability to conduct 
normal life  functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening,  or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed  in this definition 
Note: Hospital admission for a planned procedure/disease  treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant  signs consent.  SAE reporting is required 
for 30-days after the participant’s  last investigational  treatment or intervention.  Any events 
that occur after the 30-day period and that are at least possibly related to protocol treatment 
must be reported. 
 
If an SAE requires submission to the IRB office  per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical  Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include  a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.   All other reports should be sent to saemskind@ mskcc.org. 


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Page 41 of 45 
 
 
 
 
 
For all other trials: Reports that include  a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.   All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• Subject’s initials 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship  of the adverse event to the treatment  (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes  the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• If an amendment  will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated  Problem 
The PI’s signature  and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.   If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office 
 
 
17.2.1 
 
Any additional SAE reporting information required by the sponsor or drug supplier  should be 
included  in this section. 


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Page 42 of 45 
 
 
 
 
 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified  procedures are carried out, consenting professionals  will explain 
full details of the protocol and study procedures as well as the risks involved  to participants 
prior to their inclusion in the study. Participants  will also be informed  that they are free to 
withdraw from the study at any time. All participants  must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements  of the 
Code of Federal Regulations  and the Institutional  Review Board/Privacy Board of this Center. 
The consent form will include  the following: 
1. The nature and objectives, potential risks and benefits  of the intended study. 
2. The length of study and the likely follow-up  required. 
3. Alternatives  to the proposed study. (This will include  available  standard and 
investigational therapies. In addition,  patients will be offered an option of supportive 
care for therapeutic  studies.) 
4. The name of the investigator(s)  responsible  for the protocol. 
5. The right of the participant  to accept or refuse study interventions/interactions  and to 
withdraw from participation at any time. 
Before any protocol-specific  procedures can be carried out, the consenting professional  will 
fully explain the aspects of patient privacy concerning research specific  information.   In 
addition to signing the IRB Informed  Consent, all patients must agree to the Research 
Authorization component of the informed  consent form. 
Each participant  and consenting professional will sign the consent form. The participant  must 
receive a copy of the signed informed  consent form. 
 
 
19.0 
REFERENCES 
 
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Garcia AA, Blessing JA, Nolte S et al. A phase II evaluation of weekly docetaxel in the 
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20.0 
APPENDICES 
 
None 


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