Phase I Dose-Escalation Study of Combination of Gedatolisib (a Dual Inhibitor of PI3-K and mTOR) With Palbociclib and Faslodex in the Neoadjuvant Setting in Previously Untreated Patients With ER+/HER2- Breast Cancer
Phase: PHASE1
Conditions: Breast Cancer
Sponsor: Hoffman Oncology

Page 1 of 55 
CLINICAL STUDY PROTOCOL 
Phase I Dose-Escalation Study of Combination of Gedatolisib (a Dual Inhibitor of PI3-K 
and mTOR) with Palbociclib and Faslodex in the Neoadjuvant Setting in Previously 
Untreated Patients with ER+/HER2- Breast Cancer 
Protocol Number: 
CL-Gedatolisib-001
Investigational Drug: Gedatolisib (Code name PF-05212384, formerly known as PKI-587) 
US IND Number:   
128,914 
Sponsor: 
Anthony Hoffman, MD 
Hoffman Oncology
1461 Astor Avenue 
Bronx, NY 10469 
Medical Monitor: 
Anthony Hoffman, MD (718-655-1005) 
Current Version:  
October 2018 
Previous Versions:  
May 2018 
January 2017
May 2016
February 2016
January 2016, V2 
January 2016
December 2015 (Amendment 0) 
Confidentiality Statement 
The information in this document contains proprietary information that is the property of Dr. 
Anthony Hoffman of Hoffman Oncology.  This confidential information is intended solely for the 
recipient personnel related to clinical trials for evaluating and conducting clinical 
investigations.  It must not be disclosed to any other party unless such disclosure is required by 
applicable law or regulations.  Any other use will require written consent from Dr. Anthony 
Hoffman. 
NCT02626507
20152600
IRB Approved at the 
Protocol Level 
Dec 31, 2018

Investigational Product:  Gedatolisib 
Confidential and Proprietary 
Protocol#:  CL-Gedatolisib-001 (Version:  October 2018) 
Page 2 of 55 
 
STUDY SYNOPSIS 
Study Title 
(Study No.) 
Phase I Dose-Escalation Study of Combination of Gedatolisib (a Dual Inhibitor of PI3-K and mTOR) 
with Palbociclib and Faslodex in the Neoadjuvant Setting in Previously Untreated Patients with 
ER+/HER2- Breast Cancer (CL-Gedatolisib-001) 
Study 
Objectives 
The primary objectives of the current study are: 
- Safety, tolerability and potential efficacy of Gedatolisib when used in combination with palbociclib 
and Faslodex (fulvestrant), administered in the neoadjuvant setting in previously untreated patients 
with ER+/HER2- breast cancer. 
- The MTD of Gedatolisib when used in combination with palbociclib and Faslodex in these patients. 
The secondary objective of the current study is: 
- pCR induced by the Gedatolisib/palbociclib/Faslodex combination in the neoadjuvant setting in 
previously untreated patients with ER+/HER2- breast cancer. 
The exploratory objectives of the current study are: 
- To assess the baseline values, and potential correlations between the baseline values and their response 
to the investigational neoadjuvant therapy, of the genomic test Foundation CDx™ in tumor tissue and 
the genomic test FoundationOne®Liquid in peripheral whole blood. 
Study Drug Gedatolisib (Code name PF-05212384, formerly known as PKI-587) 
Study 
Design 
Dose-Escalation, Open-Label and Non-Randomization:  This is a dose-escalation Phase Ib clinical trial 
in 18 patients with newly diagnosed Stage II-III ER+/HER2- breast cancer, with the primary cancer in 
place.  These patients have not received prior therapy for their breast cancer and are intended to 
undergo surgery after four cycles of therapy. 
This is an open-label study, and investigators and subjects are not blinded to the treatment.  An open-
label study design is used because this is a dose-escalation trial and the investigators need to determine 
the potential toxicity before a decision can be made to continue the dose escalation procedures. 
The assignment of patients will not be randomized, as this is a dose-escalation trial. 
Duration of Treatment, Treatment Cycle and Study Drug Administration:  Each patient will be treated 
for a total of four treatment cycles.  Each treatment cycle is four weeks or 28 days.  During each 
treatment cycle, Gedatolisib, Palbociclib, Faslodex and, in pre-menopausal patients, Zoladex, Eligard 
or Lupron Depot, are given as outlined in Table A (next page). 
 
- Cont’d on the next page – 

Investigational Product:  Gedatolisib 
Confidential and Proprietary 
Protocol#:  CL-Gedatolisib-001 (Version:  October 2018) 
Page 3 of 55 
STUDY SYNOPSIS (cont’d) 
Study 
Design 
(cont’d) 
Table A:  Treatment with Gedatolisib, Palbociclib and Faslodex for Four 4-Week Treatment Cycles
Patient 
Type 
Drugs 
Dose Per 
Administration
Route and Administration 
Dosing Regimen 
Pre- and 
Post-
Menopausal 
Subjects 
Gedatolisib 150, 180*, 215 
or 260 mg
IV, over 30 minutes 
Once weekly for each of the four 
4-week cycles.
Palbociclib 
125 mg 
PO, with food 
Once daily on Days 1-21 for each 
of the four 4-week cycles.
Faslodex 
500 mg 
IM, into the buttocks slowly over 1-
2 minutes per injection as two 5-mL 
injections, one in each buttock.
Once daily on Days 1 and 15 of 
Cycle 1, and on Day 1 of each of 
the remaining three 4-week cycles.
Pre-
Menopausal 
Subjects 
Only 
(use any one 
of the three 
drugs 
shown) 
Zoladex 
3.6 mg 
SC, into the anterior abdominal wall 
below the navel line using an 
aseptic technique under the 
supervision of a physician.
Once every 28 days, starting 
1 week prior to treatment. 
Eligard 
7.5 mg 
SC, into the abdomen, upper 
buttocks, or another location with 
adequate area not having excessive 
pigment, nodules, lesions, or hair, 
and choose an area that hasn’t 
recently been used.  Use an aseptic 
technique according to the 
instructions stated in the Package 
Insert and under the supervision of a 
physician. 
Once monthly, starting 
1 week prior to treatment. 
Lupron 
Depot 
7.5 mg 
IM, using an aseptic technique 
according to the instructions stated 
in the Package Insert and under the 
supervision of a physician. 
Once monthly, starting 
1 week prior to treatment. 
DLT = dose-limiting toxicity; IM = intramuscular; IV = intravenous; PO = oral; SC = subcutaneous. 
* 180 mg is the starting dose in this dose-escalation study.  If DLT is observed in two or more patients in the first 
cohort at the dose level of 180 mg, the dose will be de-escalated with the dose of the next cohort reduced to 150 
mg. 
 
Dose Escalation and De-Escalation Scheme of Gedatolisib: 
 
Dose Escalation Scheme:  Gedatolisib is administered by IV once weekly during the four 4-week 
cycles, for a total of 16 weeks.  The dose will be escalated in three cohorts, at dose levels of 180 mg, 
215 mg and 260 mg.  The number of patients in each cohort will initially be three.  If no patients in 
any cohort develop a dose-limiting toxicity (DLT, defined below), dose escalation will continue in 
cohorts of three patients.  However, if a DLT is observed in a patient (whether it is the first, second 
or third of the three intended patients) at any dose level, the cohort of that dose level will be 
expanded to a maximum of six patients.  If no DLT is observed in another patient out of a maximum 
of six patients, dose escalation procedure will continue in three patients for each subsequent cohort.  
However, once a DLT is observed in a total of two patients in any cohort, dosing of Gedatolisib in 
patients at that dose level will stop immediately, even though the total number of patients at the last 
cohort may be as few as two.  Dose escalation is considered to be complete.  The dose level that 
induces a DLT in two or more patients is considered to be above MTD, and the dose level 
immediately below the dose level that induced a DLT in two or more patients is considered the 
MTD. Once the MTD has been determined, additional patients will be treated with Gedatolisib at 
MTD so that a total of 18 patients are treated in this trial. 
 
Dose De-Escalation Scheme:  If DLT is observed in two or more patients in the first cohort at the dose 
level of 180 mg, the dose for the next cohort will be reduced to 150 mg.  If DLT is also observed in 
two or more patients at 150 mg, the study will be discontinued and patients will proceed with 
standard of care treatment for breast cancer.  If DLT is observed in less than two patients at 150 mg, 
150 mg is considered the MTD.  Once the MTD has been determined, additional patients will be 
treated with Gedatolisib at MTD so that a total of 18 patients are treated in this trial. 
- Cont’d on the next page – 

Investigational Product:  Gedatolisib 
Confidential and Proprietary 
Protocol#:  CL-Gedatolisib-001 (Version:  October 2018) 
Page 4 of 55 
- Cont’d from the previous page - 
 
STUDY SYNOPSIS (cont’d) 
Study 
Design 
(cont’d) 
 
Definition of DLT:  A DLT is defined as the occurrence of any clinically relevant, grade ≥3 according 
National Cancer Institute (NCI) Common Toxicity Criteria (CTC), non-hematologic, non-infectious 
toxicity.  The following toxicities are excluded from defining a DLT: Grade 3 nausea and vomiting 
responsive to anti-emetics, Grade 3 diarrhea responsive to anti-diarrheal therapy, Grade 3 tumor lysis 
syndrome, Grade 3 or 4 metabolic derangements attributed to tumor lysis syndrome or antimicrobial 
medications that correct with oral or IV supplementation.  A DLT is also defined as the occurrence of 
Grade 3 thrombocytopenia with clinically significant bleeding (i.e., requires hospitalization, 
transfusion of blood products, or other urgent medical intervention); Grade 4 thrombocytopenia; ≥ 
Grade 3 febrile neutropenia (absolute neutrophil count <1.0×109/L and fever > 101°F/38.3°C); Grade 
4 neutropenia that does not recover to Grade ≤2 in ≤3 days after interrupting study drug; or Grade 4 
anemia not explained by underlying disease or some other concomitant disorder. 
 
When Dose Escalation Can Take Place: Dose escalation to the next dose level cannot take place until 
all patients at the previous cohort have been given a complete cycle of treatment (i.e., 4 weeks). 
 
Intra-Patient Dose Escalation Not Used:  Intra-patient dose escalation is not allowed.  Each patient can 
only participate in a single cohort. 
 
Dose Delay and Dose Modification in the Event of Adverse Events 
 
Dosing Delay and Dose Modification for Adverse Events Related to Gedatolisib and Palbociclib:  
Gedatolisib and Palbociclib dose modifications for treatment-related toxicities requiring treatment 
interruption/delay despite optimal medical treatment are described below.  The possible dose levels of 
Gedatolisib are shown in Table B (below).  For Palbociclib, the dose to be used is 125 mg.  First dose 
reduction is to 100 mg, second dose reduction is to 75 mg. 
 
Table B:  Modification of Gedatolisib Dose for Gedatolisib Related Toxicities. 
If the Gedatolisib 
Dose is: 
Available Dose of Gedatolisib for Dose Modification Due to Adverse Event 
DL-1 
DL-2 
DL-3 
150 mg 
140 mg 
130 mg 
120 mg 
180 mg 
150 mg  
140 mg 
130 mg 
215 mg 
180 mg 
150 mg  
140 mg 
260 mg 
215 mg 
180 mg 
150 mg  
NA = Not Applicable; DL-1 = first dose reduction; DL-2 = second dose reduction; DL-3 = third dose reduction. 
 
Hematologic Toxicities: 
- 
If Grade 1 or 2, then no dose modification is required.  
- 
If Grade 3 or 4 then see below for modifications of Gedatolisib and Palbociclib:  
Gedatolisib: 
- 
Withhold dose until toxicity is Grade ≤2, then resume treatment at next lower dose.  
(Note:  If the toxicity reoccurs with Grade 4 severity, withhold dose until toxicity is 
Grade ≤2, and then resume treatment at the same dose level or discontinue protocol 
directed therapy at the discretion of the Investigator.) 
Palbociclib: 
- 
Withhold Palbociclib, repeat complete blood count monitoring within 1 week. 
o 
If recovered to Grade ≤2, resume at the same dose. 
o 
If Grade 3, hold until recovery to Grade ≤2.  Resume at the same dose. 
o 
If Grade 4, hold initiation of next cycle until recovery to Grade ≤2.  Resume at the 
next lower dose. 
o 
Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 
neutropenia or recurrent Grade 3 neutropenia in subsequent cycles. 
 
- Cont’d on the next page – 

Investigational Product:  Gedatolisib 
Confidential and Proprietary 
Protocol#:  CL-Gedatolisib-001 (Version:  October 2018) 
Page 5 of 55 
- Cont’d from the previous page - 
 
STUDY SYNOPSIS (cont’d) 
Study 
Design 
(cont’d) 
 
Non-Hematologic Toxicities: 
- 
If Grade 1 or 2, no dose modification is required.  
- 
If Grade ≥ 3 (including, nausea, vomiting, diarrhea, and hypertension, and only if persisting 
despite optimal medical treatment), then: 
o 
Withhold dose of Gedatolisib and Palbociclib until toxicity is Grade ≤ 2, then resume 
treatment at next lower dose of each agent. 
o 
If the toxicity recurs with Grade 3 severity, withhold dose of Gedatolisib and Palbociclib 
until toxicity is Grade ≤2 and then resume treatment at the next lower dose of each agent 
or discontinue protocol directed therapy.* 
 
Gastrointestinal toxicities 
- 
If Grade 1 or 2, no dose modification is required.  
- 
If Grade ≥3 nausea/vomiting despite optimal antiemetic treatment, Grade 3 mucositis, or 
Grade 3 diarrhea despite optimal anti-diarrheal treatment, then: 
o 
Withhold dose of Gedatolisib and Palbociclib until toxicity is Grade ≤2, then resume 
treatment at next lower dose of each agent. 
o 
If the toxicity reoccurs with Grade 3 severity, despite optimal supportive care, withhold 
dose of Gedatolisib and Palbociclib until toxicity is Grade ≤ 2, and then resume 
treatment at next lower dose of each agent or discontinue treatment at the discretion of 
the Investigator.  
o 
Grade 4 diarrhea/mucositis, discontinue protocol directed therapy.* 
 
Metabolic toxicities 
- 
If Grade 1, no dose modification is required.  
- 
If Grade ≥2 hyperglycemia, implement hyperglycemia management.  No dose modification is 
required.  
- 
If Grade 4 hyperglycemia despite optimal anti-hyperglycemic treatment, discontinue protocol 
directed therapy.* 
 
Pneumonitis 
- 
If Grade 1, no dose modification is required.  Initiate appropriate therapy.  
- 
If Grade 2, consider interruption of therapy with Gedatolisib and Palbociclib: 
o 
Initiate clinically appropriate monitoring. 
o 
Reduce at next lower dose of each agent. 
o 
If Grade ≥ 2 toxicity recurs discontinue protocol directed therapy.* 
- If Grade 3, discontinue protocol directed therapy. 
 
Failure to recover 
- 
Patients must discontinue protocol directed therapy* after failure to recover to Grade ≤1 or 
baseline severity for drug-related toxicity (or, at the Investigator’s discretion, Grade ≤2 for 
toxicities not considered a safety risk for the patient) after delaying initiation of the next cycle 
by a maximum of 2 weeks.  
 
* At discontinuation of therapy, operable patients should proceed promptly to surgery.  
 
Dosing Delay and Dose Modification for Adverse Events Related to Faslodex:  For adverse events that 
are possibly related to faslodex, the dose modification procedures stated in the Package Inserts of 
these drugs will be followed. 
 
- Cont’d on the next page – 

Investigational Product:  Gedatolisib 
Confidential and Proprietary 
Protocol#:  CL-Gedatolisib-001 (Version:  October 2018) 
Page 6 of 55 
- Cont’d from the previous page - 
 
STUDY SYNOPSIS (cont’d) 
Inclusion/ 
Exclusion 
Criteria 
Inclusion Criteria:  Patients must meet all inclusion criteria before enrollment: 
 
A. Stage II-III, with primary cancer in place, non-inflammatory invasive breast cancer confirmed by core 
needle or incisional biopsy (excisional biopsy is not allowed): 
- 
the disease is ER+ (defined as ER expression ≥1% of invasive cancer cells according to 
immunohistochemical [IHC] staining) 
- 
HER2- (defined as IHC staining of 0 to 1+ or fluorescence in situ hybridization [FISH] ratio of 
HER2 gene copy/chromosome 17 of <2.0.) 
- 
patient’s disease is previously untreated for breast cancer, operable and patient intends to 
undergo surgery for her disease (e.g., a mastectomy or lumpectomy) after completion of 
neoadjuvant therapy 
- 
the disease must be with palpable or clinically assessable tumors in the breast 
- 
the disease must be radiographically measurable in the breast (Radiographically measurable 
disease is defined as longest diameter ≥10 mm (1.0 cm) 
- 
the disease cannot be axillary disease only (i.e., no identifiable tumor in the breast that is ≥1 cm 
on physical exam or radiographic study) 
- 
the disease can be multi-centric or bilateral disease, provided one target lesion meets the above 
eligibility criteria 
- 
breast cancer patients with lobular and luminal histology will be included.  However, patients 
with lobular histology should not be more than a quarter of the total number of patients in this 
trial, as the investigational drugs are likely to have greater activities in patients with luminal 
histology. 
(Note:  In patients with Stage III disease, PET/CT imaging studies is performed to rule out overt 
metastatic disease.  In patients with clinically positive axillae, histologic confirmation by biopsy or 
fine-needle aspiration is performed.  Patients with clinically negative axillae can undergo 
pretreatment sentinel lymph node sampling.) 
B. Females ≥18 years of age. 
C. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) 
must use effective contraceptive methods (such as abstinence, intrauterine device [IUD], or double 
barrier device) during the study and for at least 3 months following completion of the study, and must 
have a negative serum or urine pregnancy test within 2 weeks prior to treatment initiation. 
D. Mentally competent, able to understand and willingness to sign the informed consent form. 
E. At least 4 weeks must have elapsed from any prior major surgery or hormonal therapy.  The 
following procedures are not considered major surgical procedures: 
- Obtaining the required research h needle biopsies 
- Placement of a radiopaque clip to localize a tumor or tumors for subsequent surgical resection 
- Placement of a port for central venous access 
- Fine needle aspiration of a prominent or suspicious axillary lymph node 
- Needle biopsy of a clinically or radiographically detected lesion to rule out metastatic disease 
- Sampling of sentinel lymph node 
F. Laboratory values ≤2 weeks must be: 
- Adequate glycemic balance (hemoglobin A1c or glycated hemoglobin ≤8%; fasting serum glucose 
≤130 mg/dL, and fasting triglycerides ≤300 mg/dL). 
- Adequate hematology (white blood cell [WBC] ≥3500 cells/mm3 or ≥3.5 bil/L; Granulocytes ≥ 
1,000/μL; platelet count ≥100,000 cells/mm3 or ≥100 bil/L; absolute neutrophil count [ANC] 
≥1500 cells/mm3 or ≥1.5 bil/L; and hemoglobin (Hgb) ≥9 g/dL or ≥90 g/L). 
- Adequate hepatic function (aspartate aminotransferase ≤3x upper normal limit [UNL], alanine 
aminotransferase ≤3x UNL, bilirubin ≤1.5x UNL).- Adequate renal function (serum creatinine 
≤1.5 mg/dL or 133 µmol/L). 
- Adequate coagulation (International Normalized Ratio [INR] must be <1.5) 
 
- Cont’d on the next page – 

Investigational Product:  Gedatolisib 
Confidential and Proprietary 
Protocol#:  CL-Gedatolisib-001 (Version:  October 2018) 
Page 7 of 55 
- Cont’d from the previous page - 
 
STUDY SYNOPSIS (cont’d) 
Inclusion/ 
Exclusion 
Criteria 
(cont’d) 
Exclusion Criteria:  Patients with any of the following characteristics will be excluded: 
 
A. Serious medical illness, such as significant cardiac disease (e.g. symptomatic congestive heart 
failure, unstable angina pectoris, symptomatic coronary artery disease, myocardial infarction within 
the past 6 months, uncontrolled or symptomatic cardiac arrhythmia, or New York Heart Association 
Class III or IV), or severe debilitating pulmonary disease, that would potentially increase patients’ 
risk for toxicity 
B. A marked baseline prolongation of QT/QTc interval (e.g., repeated exhibition of a QTc interval 
>470 ms). 
C. A history of additional risk factors for torsade de pointes (e.g., clinically significant heart failure, 
hypokalemia, family history of Long QT Syndrome). 
D. Arterial thrombotic event, stroke, or transient ischemia attack within the past 12 months 
E. Uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure >90 
mm Hg), or peripheral vascular disease ≥grade 2 
F. Active central nervous system (CNS), epidural tumor or metastasis, or brain metastasis. 
G. Any active uncontrolled bleeding, a bleeding diathesis (e.g., active peptic ulcer disease), or a history 
of bleeding (e.g., hemoptysis, upper or lower gastrointestinal bleeding) within the past 6 months 
H. Dyspnea with minimal to moderate exertion.  Patients with large and recurrent pleural or peritoneal 
effusions requiring frequent drainage (e.g. weekly). Patients with any amount of clinically 
significant pericardial effusion. 
I. 
Diabetes of any type, except non-insulin dependent diabetes mellitus (NIDDM) that is controlled 
and with hemoglobin A1c ≤8%. 
J. Evidence of active infection during screening, or serious infection within the past month 
K. Patients with known HIV infection. 
L. Serious or non-healing wound, skin ulcer, or bone fracture 
M. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months 
N. Neuropathy of grade ≥2 
O. Albumin <2.5 g/dL or <25 g/L. 
P. Lactating females. 
Q. Any condition or abnormality which may, in the opinion of the investigator, compromise the safety 
of patients. 
R. Unwilling or unable to follow protocol requirements. 
S. Patients receiving any other standard or investigational treatment for their cancer, or any other 
investigational agent for any indication within the past 3 weeks prior to participating in the study. 
T. Requirement for immediate palliative treatment of any kind including surgery and radiation. 
Study 
Procedures 
The study procedures are outlined in Table C (next page). 
 
 
- Cont’d on the next page – 
 

Investigational Product:  Gedatolisib 
Confidential and Proprietary 
Protocol#:  CL-Gedatolisib-001 (Version:  October 2018) 
Page 8 of 55 
STUDY SYNOPSIS (cont’d) 
Table C:  Procedures for Treatment with Gedatolisib, Palbociclib and Faslodex in Each of the Four 4-Week Treatment Cycles 
Treatments and Assessments 
Screening b
Each 4-Week Treatment Cycle 
Surgery l 
Days on Week 1 
Days on Week 2 
Days on Week 3 
Days on Week 4 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
7 
Treatments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gedatolisib 
 
√ 
 
 
 
 
 
 
√
 
 
 
 
 
 
√ 
 
 
 
 
 
 
√ 
 
 
 
 
 
 
 
Palbociclib 
 
√ 
√ 
√
√ 
√
√ 
√ 
√ 
√ 
√
√ 
√ 
√ 
√ 
√ 
√ 
√
√ 
√
√ 
√ 
 
 
 
 
 
 
 
 
Faslodex 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
√a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Zoladex, Eligard or Lupron Depot (pre-menopausal patients 
only) 
Once every 28 days, starting 1 week prior to treatment. 
 
Medical history & current medication 
√
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer history c 
√
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemioglobin A1c 
√
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ k 
ECG 
√ i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam and body weight 
√ d 
√ d
 
 
 
 
 
 √ d
 
 
 
 
 
 √ d
 
 
 
 
 
 √ d
 
 
 
 
 
 
 
Vital signs and evaluation of symptoms 
√ e 
√ e
 
 
 
 
 
 
√ e
 
 
 
 
 
 
√ e
 
 
 
 
 
 
√ e
 
 
 
 
 
 
√ k 
Pregnancy test for woman of child-bearing potential 
√f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Fasting serum glucose and fasting triglycerides, as well as 
insulin, C-peptide and cholesterol 
√ g 
√ g
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ k 
- Clinical chemistry, hematology & coagulation 
√ g 
√ g
 
 
 
 
 
 √ g
 
 
 
 
 
 √ g
 
 
 
 
 
 √ g
 
 
 
 
 
 
√ k 
Tumor Response Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Radiographic tumor response assessments 
√ m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ m 
- Clinical tumor response assessments 
√ n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 √ n
 
Efficacy and Biomarkers/Genomics: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Tumor Tissues:  pCR/pCR background information and 
Foundation CDx™ 
√ h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ h 
- Blood:  FoundationOne®Liquid 
√ j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ j 
pCR = pathological complete response; WBC = white blood cells. 
a Dosing on Days 1 and 15 takes places only in Cycle 1.  Dosing in the remaining three 4-week cycles takes place on Day 1 only. 
b Screening includes medical history; current medications; cancer history; physical exam; body weight; height (screening only); vital signs; evaluation of symptoms; and blood work (clinical 
chemistry, hematology and coagulation).  Screening must be performed within two weeks prior to neoadjuvant treatment, except that radiographic tumor response assessments can be performed 
within 4 weeks prior to neoadjuvant treatment. 
c Cancer history includes: date of diagnosis, current stage of disease, date of diagnosis of the current stage of disease, and cancer-related treatment history. 
d Physical exam and body weight will be performed during screening and immediately before Gedatolisib administration.  They can be performed whenever clinically indicated.  Height will also be 
assessed during screening. 
e Vital signs and evaluation of symptoms will be performed during screening, immediately before Gedatolisib administration, and immediately after Gedatolisib administration.  They can also be 
performed whenever clinically indicated. 
f Obtain within 2 weeks prior to treatment initiation.  Also performed at least monthly in pre-menopausal women. 
g Blood work (clinical chemistry, hematology and coagulation), as well as fasting serum glucose, fasting triglycerides, insulin, C-peptide and cholesterol are assessed in the clinic.  Blood work will 
be performed at baseline, weekly and before surgery.  During neoadjuvant therapy, blood work is to be performed with results available for review within 72 hours prior to the start of treatment 
each week.  Fasting serum glucose is performed at baseline and on Day 1 of each of the four treatment cycles during neoadjuvant therapy; fasting triglycerides are performed at baseline; whereas 
insulin, C-peptide and cholesterol are performed at baseline and before surgery.  For fasting serum glucose and fasting triglycerides, patients are required to fast overnight (nothing except water 
and/or medications after midnight or for a minimum of 8 hours before the assessment).  For tests that are required before the first dose of Cycle 1, the results from screening can be used. 

Investigational Product:  Gedatolisib 
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Protocol#:  CL-Gedatolisib-001 (Version:  October 2018) 
Page 9 of 55 
 
 
h Tumor tissues are obtained at baseline via needle biopsy,and post-treatment from tumor excision surgery to assess pCR (pCR background information at baseline) and genomics via the Foundation 
CDx™ test.  Extra tumor samples, if available, are stored for possible future testing. 
i ECG is assessed at screening to exclude subjects with a marked prolongation of QT/QTc interval (e.g., repeated exhibition of a QTc interval >470 ms). 
j Whole blood samples are obtained at baseline, post-treatment (before tumor excision surgery), and at the first follow up visit after surgery for assessment of genomics via the 
FoundationOne®Liquid test.  Extra blood samples, if available, are stored in sample tubes from the sample kits provided by FoundationOne for possible future testing. 
k To be performed before surgery to ensure vital signs, symptoms and lab values are back to normal prior to surgery.  Surgery can be performed with total WBC >3,000 cells/mm3. 
l Surgery should be performed 3 weeks after completion of neoadjuvant therapy.  If surgery is delayed, the actual time of surgery in reference to completion of neoadjuvant therapy is to be recorded 
and the reason for delay (e.g., recovery from adverse effects from neoadjuvant therapy) should be documented. 
m Radiographic tumor response assessments are performed at baseline, and after 2 cycles of neoadjuvant therapy (performed on Week 4 of Cycle 2 after completion of study drug administration) 
using the same imaging modality used to obtain baseline tumor measurements.  If there is radiological evidence of disease progression, patients should be withdrawn from study and operable 
patients should proceed promptly to surgery. 
 n Clinical tumor response assessments with physical exam of the breast and axilla are performed at baseline, and at the end of each cycle during Week 4 or on Day 1 prior to the start of treatment of 
the next cycle.  Patients with Stage II-III disease who demonstrate clinical evidence of disease progression should be withdrawn from study and operable patients should proceed promptly to 
surgery. 
 
 

Investigational Product:  Gedatolisib 
Confidential and Proprietary 
Protocol#:  CL-Gedatolisib-001 (Version:  October 2018) 
Page 10 of 55 
TABLE OF CONTENTS 
1.  BACKGROUND, STUDY RATIONALE AND STUDY OBJECTIVES 
13 
1.1 Background and Study Rationale 
13 
1.2 Study Objectives 
14 
2.  STUDY DRUG - Gedatolisib 
15 
2.1 Formulation, Pharmaceutical Properties and Administration 
15 
2.2 Request for Gedatolisib Drug Product 
15 
2.3 Procurement of Investigational Drug 
15 
2.4 Disposal of Gedatolisib Drug Product 
16 
3.  STUDY SUBJECTS AND PROTECTION 
17 
3.1 Eligibility Criteria, Concomitant and Prophylactic Treatment, Registration and 
Enrollment, Identification of Study Subjects 
17 
3.2 Protection of Human Subjects 
20 
4.  STUDY DESIGN AND PROCEDURES 
22 
4.1 Study Objectives 
22 
4.2 Study Design - Dose-Escalation, Open-Label and Non-Randomization 
22 
4.3 Duration of Treatment, Treatment Cycle and Study Drug Administration 
22 
4.4 Dose Escalation and De-Escalation Scheme of Gedatolisib 
23 
4.5 Justification of the Starting Dose in the Dose Escalation Scheme 
25 
4.6 Dosing Delay and Dose Modification in the Event of Adverse Events 
25 
4.7 Withdrawal from Study 
27 
4.8 Study Procedures 
28 
4.9 Specifics of Tests Performed During the Study 
32 
4.10 
Surgery for Breast Cancer After Neoadjuvant Therapy 
34 
4.11 
Statistical Analysis 
35 
5.  GUIDELINES FOR INVESTIGATORS 
36 
5.1 Contraindications 
36 
5.2 Special Warnings and Precautions for Use 
36 
5.3 Interaction with Other Medicinal Products and other Forms of Interaction 
41 
5.4 Fertility, Pregnancy, and Lactation 
41 
5.5 Effects on Ability to Drive and Use Machines 
42 
5.6 Reference Safety Information 
42 
5.7 Overdose 
42 
5.8 Drug Abuse and Dependence 
43 
6.  ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
44 
6.1  Adverse Events 
44 
6.2  Adverse Event Grading, Recording and Reporting 
44 
6.3  Serious Adverse Events 
45 
6.4  Serious Adverse Event Recording and Reporting 
46 
7.  COMPLIANCE, PROTOCOL AMENDMENT, AND DATA MANAGEMENT 
47 
7.1  Compliance 
47 
7.2  Protocol Amendments 
47 
7.3  CRFs 
47 
7.4  Data Entry 
47 
7.5  Record Maintenance 
48 
8.  PATIENT AND STUDY DISCONTINUATION 
49 

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9.  REFERENCES 
50 
APPENDICES 
51 
Appendix D: Sampling and Shipment Procedures for FoundationOne CDx 
52 
Appendix B: Sampling and Shipment Procedures for FoundationOne®Liquid 
55 
 
 
Abbreviations 
AC 
= ante clbum (before meals) 
AE 
= adverse events 
ADR 
= adverse drug reactions 
AJCC 
= American Joint Committee on Cancer 
ALT 
= alanine aminotransferase 
ALP 
= alkaline phosphatase 
ANC 
= absolute neutrophil count 
ASCO 
= American Society of Clinical Oncology 
AST 
= aspartate aminotransferase 
ATP 
= Adenosine triphosphate 
BUN 
= blood urea nitrogen 
CBC 
= complete blood counts 
CDK 
= cyclin-dependent kinase 
CDx 
= companion diagnostic 
CFR 
= Code of Federal Regulations 
CNB 
= Core Needle Biopsy 
CNS 
= central nervous system 
CRF 
= case report form 
CTC 
= common toxicity criteria 
DFS 
= disease-free survival 
DLT 
= dose-limiting toxicity 
DM 
= Diabetes Mellitus 
ER+ 
= estrogen receptor positive 
FBG 
= fasting blood glucose 
FDA 
= Food and Drug Administration 
FFPE 
= Formalin-fixed, paraffin-embedded 
FISH 
= fluorescence in situ hybridization 
GCP 
= Good Clinical Practices 
G-CSF 
= granulocyte colony stimulating factor 
HER2- 
= human epidermal growth factor receptor 2 negative 
Hgb 
= hemoglobin 
IHC 
= immunohistochemical 
IM 
= intramuscular or intramuscularly 
IND 
= Investigational New Drug 
INR 
= International Normalized Ratio 
IRB 
= Institutional Review Board 
IUD 
= intrauterine device 
IV 
= intravenous or intravenously  
LDH 
= lactate dehydrogenase 

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MEK 
= MAPK/ERK kinase 
MSI 
- microsatellite instability 
mTOR 
= mammalian target of rapamycin 
MTD 
= maximum tolerated dose 
NCI 
= National Cancer Institute 
NIDDM 
= non-insulin dependent diabetes mellitus 
p-Akt 
= phosphorylated Akt 
PCA 
= patient controlled analgesia 
pCR 
= pathological Complete Response 
PFS 
= progression-free survival 
PI3-K 
= phosphatidylinositol-4,5-bisphosphate 3-kinase 
PIK3CA 
= phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha 
PO 
= oral or orally 
QD 
= once daily 
RPPA 
= Reverse-Phase Protein Array 
RSA 
= Research Study Assistant 
SC 
= subcutaneous or subcutaneously 
SAE 
= serious adverse event 
SGOT 
= serum glutamic-oxaloacetic transaminase 
SGPT 
= serum glutamic-pyruvic transaminase 
TLS 
= tumor lysis syndrome 
TMB 
= tumor mutational burden 
UNL 
= upper normal limit 
WBC 
= white blood cell 

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1.  BACKGROUND, STUDY RATIONALE AND STUDY OBJECTIVES 
 
1.1 Background and Study Rationale 
 
Palbociclib (Ibrance®) is an orally active highly selective reversible inhibitor of cyclin-
dependent kinase (CDK) 4 and CDK 6.  Faslodex® (Fulvestrant) is a potent anti-estrogen drug 
that binds and degrades estrogen receptors (ERs).  Interim results from the Phase 3 trial (Study 
PALOMA-3) have shown that combination of palbociclib and Faslodex increases progressive-
free survival (PFS) from 3.8 to 9.2 months in patients with metastatic estrogen receptor 
positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer 
that progressed during or after anti-endocrine therapy (Turner et al. 2015).  The 
palbociclib/Faslodex combination was found to be well tolerated.  Additionally, there is 
growing data indicating that this combination can be safely and effectively administered up 
front in anti-endocrine therapy-naive patients in the neoadjuvant setting. 
 
Gedatolisib (code name PF-05212384, formerly known as PKI-587) is an intravenous (IV) 
adenosine triphosphate (ATP) competitive, highly selective and potent inhibitor of pan-class I 
isoform phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3-K) and mammalian target of 
rapamycin (mTOR) (Fry et al. 2004).  Preclinical and first-in-human studies have shown a 
manageable safety profile with predictable toxicity for this class of drugs. 
 
Activation of the PI3-K/Akt/mTOR/p-S6 pathway has been associated with endocrine 
resistance in ER+ breast cancer.  There is ample evidence that inhibition of this pathway, in 
combination with anti-hormonal therapy, increases PFS (Baselga et al. 2012).  There is also 
clinical evidence that combination therapy targeting all three pathways is feasible, safe and 
effective (Sweeney et al. 2014).  The advantage of Gedatolisib is its potential to inhibit 
signaling through different PI3-K isoforms.  Also important is the fact that once a week 
administration may be as effective, but less toxic, than chronic oral dosing.  If hyperglycemia 
is a surrogate for effective PI3-K/Akt/mTOR/p-S6 inhibition, once weekly dosing of 
Gedatolisib would appear to accomplish equivalent degrees of hyperglycemia as chronically 
oral dosing and with less toxicity. 
 
Preoperative or neoadjuvant systemic chemotherapy, once reserved for patients with locally 
advanced breast cancer in whom the goal was to render large breast cancers operable, has 
become increasingly common due to the improvement in disease-free survival and overall 
survival.  Historically, the endpoint of pathological Complete Response (pCR) in neoadjuvant 
therapy against ER+/HER2- breast cancer has been of limited value.  However, new targeted 
agents, with higher response rates, have the potential to use pCR assessment as a strong 
clinical endpoint in drug development.  Given the systemic response rate in previously treated 
Stage IV breast cancer patients, the expectation will be a similar high rate of pathological 
improvement which can lead to greater use of targeted agents in the neoadjuvant setting. 
 
In addition to the potential of better pathological improvement, the advantage of clinical 
studies involving neoadjuvant therapy is that they can provide response information in patients 
that are treatment-naïve.  This type of clinical trial can also be used to assess cellular and 
molecular changes with serial biopsies while on neoadjuvant therapy, which can aid in 

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development of companion tissue and/or imaging biomarkers, and further the development of 
preclinical models. 
 
Accordingly, this investigation assesses the safety and efficacy of the combination of 
Gedatolisib, palbociclib and faslodex in the neoadjuvant setting in previously untreated 
patients with ER+/HER2- breast cancer.  Being the first clinical trial using this combination in 
neoadjuvant setting, one of the main objectives for the current trial is to determine the 
Maximum Tolerated Dose (MTD) of Gedatolisib when used in combination with palbociclib 
and faslodex.  Subsequent Phase II clinical trials will be conducted to assess the safety and 
efficacy of the Gedatolisib/palbociclib/faslodex combination, with the dose of Gedatolisib 
being the MTD determined from the current trial. 
 
1.2 Study Objectives 
 
The primary objectives of the current study are: 
 
- 
Safety, tolerability and potential efficacy of Gedatolisib when used in combination with 
palbociclib and Faslodex, administered in the neoadjuvant setting in previously untreated 
patients with ER+/HER2- breast cancer. 
- 
The MTD of Gedatolisib when used in combination with palbociclib and Faslodex in these 
patients. 
 
The secondary objective of the current study is: 
 
- 
pCR induced by the Gedatolisib/palbociclib/Faslodex combination in the neoadjuvant 
setting in previously untreated patients with ER+/HER2- breast cancer. 
 
The exploratory objectives of the current study are: 
 
- To assess the baseline values, and potential correlations between the baseline values and 
their response to the investigational neoadjuvant therapy, of the genomic test Foundation 
CDx™ in tumor tissue and the genomic test FoundationOne®Liquid in peripheral whole 
blood. 

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2.  STUDY DRUG - Gedatolisib 
 
2.1 Formulation, Pharmaceutical Properties and Administration 
 
Gedatolisib drug product is lyophilized powder (or cake) in a glass vial.  This formulation 
contains 50 mg/mL Gedatolisib and precedented excipients, with appropriate packaging. 
 
Gedatolisib drug product is to be reconstituted using an appropriate volume of sterile Water for 
Injection.  After reconstitution, the solution is added to an appropriate volume of 5% Dextrose 
for Injection prior to administration as an IV infusion. 
 
Under ambient light and room temperature conditions, the reconstituted solution can be stored 
for up to four hours and the prepared dosing solution for up to 24 hours. 
 
As with all parenteral products, the preparation and administration of Gedatolisib drug product 
in the clinic should be conducted with appropriate aseptic technique and the infusion 
commenced as soon as practical, but no longer than four hours after drug product 
reconstitution or 24 hours after dilution with 5% dextrose injection. 
 
Gedatolisib drug product is incompatible with sodium chloride and chloride ion-containing 
medication.  The use of saline and other chloride containing medication should be avoided 
during preparation and administration of Gedatolisib drug product. 
 
Gedatolisib drug product, at escalating doses of 180, 215 and 260 mg, is to be administered as 
an IV infusion over 30 minutes once weekly in 28-day cycles for a total of four cycles. 
 
2.2 Request for Gedatolisib Drug Product 
 
Complete the Drug Supply Request Form provided by Pfizer, Inc.  The Drug Supply Request 
Form lists the required information and contact information for requesting Gedatolisib drug 
product. 
 
The Principal Investigator should maintain a drug inventory sufficient to treat study subjects 
for approximately four (4) weeks while waiting for additional ordered supplies. 
 
Gedatolisib may not be used outside the scope of this protocol, nor can it be transferred or 
licensed to any party not participating in this clinical study. 
 
2.3 Procurement of Investigational Drug 
 
Relevant regulations require investigators to establish a record of the receipt, use and 
disposition of all investigational products.  Investigators may delegate responsibility of drug 
ordering, storage, accountability and preparation to the designees. 
 
The investigator, or the designee, will be responsible for dispensing and accounting of 
Gedatolisib drug product and for exercising accepted medical and pharmacy practices. 

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Records of inventory, dispensation and disposition (vials received, source and dates) must be 
maintained.  In addition, all doses dispensed should be accounted for by recording the date, 
study number and name, patient identification, patient initials, patient medical record number 
and balance forward.  These records must be maintained and kept at the study site. 
 
2.4 Disposal of Gedatolisib Drug Product 
 
The following procedures are to be taken in disposal of Gedatolisib drug product: 
 
- 
During the study, store the used Gedatolisib vials (which must be separate from the unused 
Gedatolisib vials) at room temperature in an access-limited area.  Alternatively, destroy the 
used Gedatolisib vials according to institutional policy after documentation of the number 
of used Gedatolisib vials and remaining volume in each used vial. 
- 
At the end of the study, deface the label (both used and unused vials) with a permanent 
marking pen. 
- 
For used Gedatolisib vials (if not already destroyed according to institutional policy), after 
documentation of the number of used Gedatolisib units and remaining volume in each 
container, the used containers should be destroyed at the site according to the institutional 
procedures for destroying toxic chemicals.  A certificate documenting the destruction of 
used vials must be kept on file. 
- 
All unused Gedatolisib vials must be destroyed according to the policy of the institution.  
The destruction of Gedatolisib, and the quantity destroyed, must be documented. 

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3.  STUDY SUBJECTS AND PROTECTION 
 
3.1 Eligibility Criteria, Concomitant and Prophylactic Treatment, Registration and 
Enrollment, Identification of Study Subjects 
 
3.1.1 Eligibility Criteria 
 
Inclusion Criteria:  Patients must meet all inclusion criteria before enrollment: 
 
A. Stage II-III, with primary cancer in place, non-inflammatory invasive breast cancer 
confirmed by core needle or incisional biopsy (excisional biopsy is not allowed): 
- 
the disease is ER+ (defined as ER expression ≥1% of invasive cancer cells 
according to immunohistochemical [IHC] staining) 
- 
HER2- (defined as IHC staining of 0 to 1+ or fluorescence in situ hybridization 
[FISH] ratio of HER2 gene copy/chromosome 17 of <2.0.) 
- 
the disease is previously untreated for breast cancer, operable and intended to 
undergo surgery for her disease (e.g., a mastectomy or lumpectomy) after 
completion of neoadjuvant therapy 
- 
the disease must be with palpable or clinically assessable tumors in the breast 
- 
the disease must be radiographically measurable in the breast.  (Radiographically 
measurable disease is defined as longest diameter ≥10 mm (1.0 cm) 
- 
the disease cannot be axillary disease only (i.e., no identifiable tumor in the breast 
that is ≥1 cm on physical exam or radiographic study) 
- 
the disease can be multi-centric or bilateral disease, provided the target lesion meets 
the above eligibility criteria 
- 
breast cancer patients with lobular and luminal histology will be included.  
However, patients with lobular histology should not be more than a quarter of the 
total number of patients in this trial, as the investigational drugs are likely to have 
greater activities in patients with luminal histology. 
(Note 1:  In patients with Stage III disease, PET/CT imaging studies are performed to 
rule out overt metastatic disease.  In patients with clinically positive axillae, 
histologic confirmation by biopsy or fine-needle aspiration is performed.  Patients 
with clinically negative axillae can undergo pretreatment sentinel lymph node 
sampling.) 
B. Females ≥18 years of age. 
C. Women of child-bearing potential (i.e., women who are pre-menopausal or not 
surgically sterile) must use effective contraceptive methods (such as abstinence, 
intrauterine device [IUD], or double barrier device) during the study and for at least 3 
months following completion of the study, and must have a negative serum or urine 
pregnancy test within 2 weeks prior to treatment initiation. 
D. Mentally competent, able to understand and willingness to sign the informed consent 
form. 
E. At least 4 weeks must have elapsed from any prior major surgery or hormonal therapy. 
The following procedures are not considered major surgical procedure: 
- Obtaining the required research needle biopsies 
- Placement of a radiopaque clip to localize a tumor or tumors for subsequent 

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surgical resection 
- Placement of a port for central venous access 
- Fine needle aspiration of a prominent or suspicious axillary lymph node 
- Needle biopsy of a clinically or radiographically detected lesion to rule out 
metastatic disease 
- Sampling of sentinel lymph node 
F. Laboratory values ≤2 weeks must be: 
- 
Adequate glycemic balance (hemoglobin A1c or glycated hemoglobin ≤8%; fasting 
serum glucose ≤130 mg/dL, and fasting triglycerides ≤300 mg/dL). 
- 
Adequate hematology (white blood cell [WBC] ≥3500 cells/mm3 or ≥3.5 bil/L; 
Granulocytes ≥ 1,000/μL; platelet count ≥100,000 cells/mm3 or ≥100 bil/L; 
absolute neutrophil count [ANC] ≥1500 cells/mm3 or ≥1.5 bil/L; and hemoglobin 
(Hgb) ≥9 g/dL or ≥90 g/L). 
- 
Adequate hepatic function (aspartate aminotransferase [AST/SGOT] ≤3x upper 
normal limit [UNL], alanine aminotransferase [ALT/SGPT] ≤3x UNL, bilirubin 
≤1.5x UNL). 
- 
Adequate renal function (serum creatinine ≤1.5 mg/dL or 133 µmol/L). 
- 
Adequate coagulation (International Normalized Ratio [INR] must be <1.5) 
 
Exclusion Criteria:  Patients with any of the following characteristics will be excluded: 
 
A. Serious medical illness, such as significant cardiac disease (e.g. symptomatic 
congestive heart failure, unstable angina pectoris, symptomatic coronary artery disease, 
myocardial infarction within the past 6 months, uncontrolled or symptomatic cardiac 
arrhythmia, or New York Heart Association Class III or IV), or severe debilitating 
pulmonary disease, that would potentially increase patients’ risk for toxicity 
B. A marked baseline prolongation of QT/QTc interval (e.g., repeated exhibition of a QTc 
interval >470 ms). 
C. A history of additional risk factors for torsade de pointes (e.g., clinically significant 
heart failure, hypokalemia, family history of Long QT Syndrome). 
D. Arterial thrombotic event, stroke, or transient ischemia attack within the past 12 months 
E. Uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic blood 
pressure >90 mm Hg), or peripheral vascular disease ≥grade 2 
F. Active central nervous system (CNS), epidural tumor or metastasis, or brain metastasis. 
G. Any active uncontrolled bleeding, a bleeding diathesis (e.g., active peptic ulcer 
disease), or a history of bleeding (e.g., hemoptysis, upper or lower gastrointestinal 
bleeding) within the past 6 months 
H. Dyspnea with minimal to moderate exertion.  Patients with large and recurrent pleural 
or peritoneal effusions requiring frequent drainage (e.g. weekly). Patients with any 
amount of clinically significant pericardial effusion. 
I. Diabetes of any type, except non-insulin dependent diabetes mellitus (NIDDM) that is 
controlled and with hemoglobin A1c ≤8%. 
J. Evidence of active infection during screening, or serious infection within the past 
month 
K. Patients with known HIV infection. 

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L. Serious or non-healing wound, skin ulcer, or bone fracture 
M. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the 
past 6 months 
N. Neuropathy of grade ≥2 
O. Albumin <2.5 g/dL or <25 g/L. 
P. Lactating females. 
Q. Any condition or abnormality which may, in the opinion of the investigator, 
compromise the safety of patients. 
R. Unwilling or unable to follow protocol requirements. 
S. Patients receiving any other standard or investigational treatment for their cancer, or 
any other investigational agent for any indication within the past 3 weeks prior to 
participating in the study. 
T. Requirement for immediate palliative treatment of any kind including surgery and 
radiation. 
 
3.1.2 Concomitant Medications and Prophylactic Treatment 
 
Patients cannot receive any standard or investigational treatment (except those related to this 
study) for their cancer, or any other investigational drugs for any indications, while on this 
study.  All concomitant medications (including trade and generic names, dosage and dosing 
schedule) must be recorded. 
 
Prophylactic treatment for Gedatolisib-related symptoms is not planned, or it will interfere 
with the assessment of the toxicity of the investigational product.  However, following the 
evaluation of the causal relationship of the symptom(s) to the study drug and the information 
has been documented, the investigator may prescribe supportive treatment.  Supportive 
treatment may include anti-emetic, anti-diarrhea, anti-pyretic, anti-allergic, anti-hypertensive 
medications, analgesics, antibiotics, allopurinol, granulocyte colony stimulating factor (G-
CSF) and others such as blood products at the discretion of the treating physicians.  Also, the 
hemoglobin should be maintained ≥9 g/dL or ≥90 g/L during the course of the study. 
 
Since oral mucositis was observed in ~50% of patients treated with the PF-05212384/ 
cisplatln combination, the general guidelines as concomitant treatments in the prophylaxis 
and management of oral mucositis are outlined below: 
 
Oral Mucositis - General Guidelines for Prophylaxis, Concomitant Treatments, and 
Management 
- Patients who have not had a dental checkup within 6 mos prior to start of dosing are 
encouraged to do so. 
- Patient should perform a steroid containing "swish-and-spit” regimen (e.g., 
dexamethasone 0.5 mg/5 mL swish and expectorate, four times daily.) 
• Pre-dose on Cycle 1 Day 1 as prevention and use on a continued basis as clinically 
indicated. 
• The daily number of steroid containing mouth rinses can be reduced as clinically 
indicated. 

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- Topical anesthetics or systemic analgesics may be used as indicated according to the 
judgment of the investigator and according to local clinical practices. 
- Use of chlorhexidine is to be avoided. 
 
Additionally, skin rashes have been reported in patients treated with Gedatolisib alone, and 
when Gedatolisib is used in combination with irinotecan, FOLFIRI, PD-0325901, docetaxel, 
cisplatin, or dacomitinib.  Benadryl can be given approx. 30 minutes prior to infusion of 
Gedatolisib. 
 
3.1.3 Registration, Pre-Enrollment Medical Screening and Enrollment of Study Subjects  
 
Patients Registration 
 
At the time of registration, the eligibility checklist is reviewed, verified and signed.  If the 
eligibility requirements are satisfied, the patient can be considered for pre-enrollment 
medical screening (see next section). 
 
Pre-Enrollment Medical Screening 
 
Informed consent must be obtained prior to pre-enrollment medical screening.  
Investigators who are listed on US “FDA Form 1572” (or investigator's designee) are 
authorized to obtain informed consent.  Pre-enrollment medical screening is used to 
determine the eligibility of each candidate, and it is to be performed within two weeks prior 
to neoadjuvant treatment, except that radiographic tumor response assessments can be 
performed within 4 weeks. 
 
Subject Enrollment 
 
Patients meeting all criteria stated in Section 3.1.1 are eligible for admission to the study. 
 
3.1.4  Identification of Study Subjects 
 
In addition to the study number, each study site will be assigned a site number or code.  
Furthermore, at the inception of the study, study subjects will be sequentially assigned 
numbers (e.g., 001, 002, 003, etc.) in the order of study entry at their respective site.  
Therefore, the subject will be identified by "study number - study site/code - study subject 
number". 
 
3.2 Protection of Human Subjects 
 
3.2.1  Institutional Review Board (IRB) 
 
Before implementing this study, the protocol, informed consent and any amendments must be 
reviewed and approved by an IRB.  A copy of the IRB approval letter must be provided to 
Dr. Anthony Hoffman or the designee.  Until such written approval from the IRB has been 
received by the investigator and a copy provided to Dr. Anthony Hoffman or the designee, 

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and until the proper submission of appropriate documents to the regulatory agencies and 
other regulatory requirements have been met, no patient should undergo any procedures for 
the purpose of determining eligibility for this study. 
 
3.2.2  Informed Consent  
 
Patients will be required to sign a statement of informed consent, which meets Good Clinical 
Practices (GCP) and local regulatory requirements (e.g., U.S. 21 Code of Federal 
Regulations [CFR] 50).  The medical record will include a statement indicating that written 
informed consent has been obtained, and the date informed consent is obtained, before 
enrollment in the study.  Members of the treating team (such as those listed in the FDA Form 
1572 or Canadian “Clinical Trial Site Information Form” if applicable), or investigator’s 
designee (such as the study nurse), will review to the patients the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits, and 
alternative therapies (including best supportive care).  Patients must be informed that 
participation in the study is voluntary, he/she may withdraw from the study at any time, and 
withdrawal from the study will not affect his/her subsequent medical treatment or 
relationship with the treating physician.  Financial costs that will or may be incurred as a 
result of participation in the study, as well as the efforts to maintain patient confidentiality 
will also be discussed.  The informed consent will be signed by the patient and registering 
physician (or investigator’s designee such as the study nurse).  A signed copy will be given to 
the patient.  The original will be placed in the medical record at the study site. 
 
3.2.3 Protection of Privacy 
 
The investigator agrees to maintain in confidence all data generated in the study, except as 
provided or required by law, and will divulge such information to the IRB with the 
understanding that confidentially will be maintained. 

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4.  STUDY DESIGN AND PROCEDURES 
 
4.1 Study Objectives 
 
The primary objectives of the current study are to determine: 
 
- 
Safety, tolerability and potential efficacy of Gedatolisib when used in combination with 
palbociclib and Faslodex, administered in the neoadjuvant setting in previously untreated 
patients with ER+/HER2- breast cancer. 
- 
The MTD of Gedatolisib when used in combination with palbociclib and Faslodex in the 
neoadjuvant setting in these patients. 
 
The secondary objective of the current study is: 
 
- 
pCR induced by the Gedatolisib/palbociclib/Faslodex combination in the neoadjuvant 
setting in previously untreated patients with ER+/HER2- breast cancer. 
 
The exploratory objectives of the current study are: 
 
- 
To assess the baseline values, and potential correlations between the baseline values and 
their response to the investigational neoadjuvant therapy, of the genomic test Foundation 
CDx™ in tumor tissue and the genomic test FoundationOne®Liquid in peripheral whole 
blood. 
 
4.2 Study Design - Dose-Escalation, Open-Label and Non-Randomization 
 
This is a dose-escalation Phase Ib clinical trial in 18 patients with newly diagnosed Stage II-III 
ER+/HER2- breast cancer, with the primary cancer in place.  These patients have not received 
prior therapy for their breast cancer and intend to undergo surgery after four cycles of therapy. 
 
This is an open-label study, and investigators and subjects are not blinded to the treatment.  
The reason for using an open-label study design is because this is a dose-escalation trial, and 
the investigators need to determine the potential toxicity before a decision can be made to 
continue the dose escalation procedures. 
 
The assignment of patients will not be randomized, as this is a dose-escalation trial. 
 
4.3 Duration of Treatment, Treatment Cycle and Study Drug Administration 
 
Each patient will be treated for a total of four treatment cycles.  Each treatment cycle is four 
weeks or 28 days.  During each treatment cycle, Gedatolisib, Palbociclib, Faslodex and, in pre-
menopausal patients, Zoladex, Eligard or Lupron Depot are given as outlined in Table 4.3-1 
(below).   

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Table 4.3-1:  Treatment with Gedatolisib, Palbociclib and Faslodex for Four 4-Week Treatment Cycles 
Patient 
Type 
Drugs 
Dose Per 
Administration
 
Route and Administration 
 
Dosing Regimen 
Pre- and Post-
Menopausal 
Subjects 
Gedatolisib 150, 180*, 215 
or 260 mg 
IV, over 30 minutes 
Once weekly for each of the four 
4-week cycles. 
Palbociclib 
125 mg 
PO, with food 
Once daily on Days 1-21 for each 
of the four 4-week cycles. 
Faslodex 
500 mg 
IM, into the buttocks slowly over 
1-2 minutes per injection as two 5-
mL injections, one in each buttock
Once daily on Days 1 and 15 of 
Cycle 1, and on Day 1 of each of 
the remaining three 4-week cycles.
Pre-
Menopausal 
Subjects Only 
(use any one of 
the three drugs 
shown) 
Zoladex 
3.6 mg 
SC, into the anterior abdominal 
wall below the navel line using an 
aseptic technique under the 
supervision of a physician 
Once every 28 days, starting 
1 week prior to treatment. 
Eligard 
7.5 mg 
SC, into the abdomen, upper 
buttocks, or another location with 
adequate area not having excessive 
pigment, nodules, lesions, or hair, 
and choose an area that hasn’t 
recently been used.  Use an aseptic 
technique according to the 
instructions stated in the Package 
Insert and under the supervision of 
a physician. 
Once monthly, starting 
1 week prior to treatment. 
Lupron 
Depot 
7.5 mg 
IM, using an aseptic technique 
according to the instructions stated 
in the Package Insert and under the 
supervision of a physician. 
Once monthly, starting 
1 week prior to treatment. 
DLT = dose-limiting toxicity; IM = intramuscular or intramuscularly; IV; intravenous or intravenously; PO = oral or 
orally; SC = subcutaneous or subcutaneously. 
* 180 mg is the starting dose in this dose-escalation study.  If DLT is observed in two or more patients in the first 
cohort at the dose level of 180 mg, the dose will be de-escalated with the dose of the next cohort reduced to 150 
mg. 
 
 
Specifically, the four drugs are administered as outlined below: 
 
- 
Gedatolisib at escalating doses of 180, 215 and 260 mg via a 3-6 dose-escalation scheme is 
administered once weekly on the first day for each of the four weeks during the four 4-
week cycles. 
- 
Faslodex at 500 mg is administered IM into the buttocks slowly (over 1 - 2 minutes per 
injection) as two 5-mL injections, one in each buttock, on Days 1 and 15 of Cycle 1 and on 
Day 1 of the remaining three 4-week treatment cycles. 
- 
Palbociclib at 125 mg is administered PO with food daily on Days 1-21 for each of the four 
4-week cycles. 
- 
Zoladex, Eligard or Lupron is used to render menopause in pre-menopausal subjects, given 
once every 28 days or monthly starting 1 week prior to treatment. 
 
4.4 Dose Escalation and De-Escalation Scheme of Gedatolisib 
 
Dose Escalation Scheme:  Gedatolisib is administered by IV once weekly during the four 4-

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week cycles, for a total of 16 weeks.  The dose will be escalated in three cohorts, at dose 
levels of 180 mg, 215 mg and 260 mg.  The number of patients in each cohort will initially 
be three.  If no patients in any cohort develop a dose-limiting toxicity (DLT, defined below), 
dose escalation will continue in cohorts of three patients.  However, if a DLT is observed in a 
patient (whether it is the first, second or third of the three intended patients) at any dose 
level, the cohort of that dose level will be expanded to a maximum of six patients.  If no DLT 
is observed in another patient out of a maximum of six patients, dose escalation procedure 
will continue in three patients for each subsequent cohort.  However, once a DLT is observed 
in a total of two patients in any cohort, dosing of Gedatolisib in patients at that dose level 
will stop immediately, even though the total number of patients at the last cohort may be as 
few as two.  Dose escalation is considered to be complete.  The dose level that induces a 
DLT in two or more patients is considered to be above MTD, and the dose level immediately 
below the dose level that induced a DLT in two or more patients is considered the MTD.  
Once the MTD has been determined, additional patients will be treated with Gedatolisib at 
MTD so that a total of 18 patients are treated in this trial. 
 
Dose De-Escalation Scheme:  If DLT is observed in two or more patients in the first cohort at 
the dose level of 180 mg, the dose for the next cohort will be reduced to 150 mg. (i.e., Level -
1).  If DLT is also observed in two or more patients at 150 mg (i.e., Level -1), the study will 
be discontinued and patients will proceed with standard of care treatment for breast cancer.  
If DLT is observed in less than two patients at 150 mg, 150 mg will be considered the MTD.  
Once the MTD has been determined, additional patients will be treated with Gedatolisib at 
MTD so that a total of 18 patients are treated in this trial. 
 
Definition of DLT:  A DLT is defined as the occurrence of any clinically relevant, grade ≥3 
according National Cancer Institute (NCI) Common Toxicity Criteria (CTC), non-
hematologic, non-infectious toxicity.  The following toxicities are excluded from defining a 
DLT: Grade 3 nausea and vomiting responsive to anti-emetics, Grade 3 diarrhea responsive 
to anti-diarrheal therapy, Grade 3 tumor lysis syndrome, Grade 3 or 4 metabolic 
derangements attributed to tumor lysis syndrome or antimicrobial medications that correct 
with oral or IV supplementation.  A DLT is also defined as an occurrence of Grade 3 
thrombocytopenia with clinically significant bleeding (i.e., requires hospitalization, 
transfusion of blood products, or other urgent medical intervention); Grade 4 
thrombocytopenia; ≥ Grade 3 febrile neutropenia (absolute neutrophil count <1.0×109/L and 
fever > 101°F/38.3°C); Grade 4 neutropenia that does not recover to Grade ≤2 in ≤3 days 
after interrupting study drug; or Grade 4 anemia not explained by underlying disease or some 
other concomitant disorder. 
 
When Dose Escalation Can Take Place: Dose escalation to the next dose level cannot take 
place until all patients at the previous cohort have been given a complete cycle of treatment 
(i.e., 4 weeks). 
 
Intra-Patient Dose Escalation Not Used:  Intra-patient dose escalation is not allowed.  Each 
patient can only participate in a single cohort. 
 

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4.5 Justification of the Starting Dose in the Dose Escalation Scheme 
 
The current study investigates, among other objectives, safety and tolerability of weekly IV 
escalating doses of Gedatolisib at 180 mg, 215 mg and 260 mg, when used in combination 
with Palbociclib and Faslodex, in previously untreated patients with ER+/HER2- breast cancer 
prior to tumor excisional surgery.  Patients will receive four 4-week cycles of the neoadjuvant 
therapy. 
 
The starting dose of 180 mg is expected to be safe, based on interim results from ongoing 
clinical trials, as described below.   
 
A Phase 1 single agent trial has been conducted with weekly IV administration of Gedatolisib 
in dose-escalation manner in patients with solid tumor (Study B2151001, ClinicalTrials.gov 
Identifier NCT00940498).  This study did not include doses between 154 and 222 mg.  
Therefore, the MTD of Gedatolisib is in this dose range. 
 
A Phase 1b dose-escalation trial, in which weekly IV administration of Gedatolisib in dose-
escalation manner is used in combination with various different anti-tumor agents in patients 
with solid tumor, is ongoing (Study# B2151002, ClinicalTrials.gov Identifier NCT01920061). 
Interim results show that, when used in combination with 75 mg/m2 cisplatin, Gedatolisib at 
doses of 154 mg, 180 mg, 215 mg and 260 mg is free of DLT and well tolerated.  The safety 
and tolerability of 315 mg of Gedatolisib is currently being tested. Therefore, the MTD of 
Gedatolisib when used in combination with these drugs is above 260 mg. 
 
When used in combination with 75 mg/m2 docetaxel, Gedatolisib at doses up to 180 mg is free 
of DLT in a recent clinical trial.  Doses higher than 180 mg were not tested due to termination 
of the trial because of a change in priority. 
 
Since safety and tolerability of Gedatolisib is established at doses as high as 215 mg when used 
in combination with 75 mg/m2 cisplatin, and as high as 180 mg when used in combination with 
75 mg/m2 docetaxel, Gedatolisib at the starting dose of 180 mg is expected to be safe. 
 
4.6 Dosing Delay and Dose Modification in the Event of Adverse Events 
 
4.6.1  Dosing Delay and Dose Modification for Adverse Events Related to Gedatolisib and 
Palbociclib 
 
Gedatolisib and Palbociclib dose modifications for treatment-related toxicities requiring 
treatment interruption/delay despite optimal medical treatment are described below.  The 
possible dose levels of Gedatolisib are shown in Table 4.6.1-1 (below).  For Palbociclib, the 
dose to be used is 125 mg.  First dose reduction is to 100 mg, second dose reduction is to 75 
mg. 

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Table 4.6.1-1:  Modification of Gedatolisib Dose for Gedatolisib Related Toxicities 
If the Gedatolisib 
Dose is: 
Available Dose of Gedatolisib for Dose Modification Due to Adverse Event
DL-1
DL-2
DL-3 
150 mg 
140 mg
130 mg
120 mg 
180 mg 
150 mg
140 mg
130 mg 
215 mg 
180 mg
150 mg
140 mg 
260 mg 
215 mg
180 mg
150 mg 
NA = Not Applicable; DL-1 = first dose reduction; DL-2 = second dose reduction; DL-3 = third dose reduction. 
 
 
Hematologic Toxicities: 
- 
If Grade 1 or 2, then no dose modification is required.  
- 
If Grade 3 or 4 then see below for modifications of Gedatolisib and Palbociclib:  
Gedatolisib: 
- 
Withhold dose until toxicity is Grade ≤2, then resume treatment at next lower 
dose.  (Note:  If the toxicity reoccurs with Grade 4 severity, withhold dose until 
toxicity is Grade ≤2, and then resume treatment at the same dose level or 
discontinue protocol directed therapy at the discretion of the Investigator.) 
Palbociclib: 
- 
Withhold Palbociclib, repeat complete blood count monitoring within 1 week. 
o If recovered to Grade ≤2, resume at the same dose. 
o If Grade 3, hold until recovery to Grade ≤2.  Resume at the same dose. 
o If Grade 4, hold initiation of next cycle until recovery to Grade ≤2.  Resume at 
the next lower dose. 
o Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 
3 neutropenia or recurrent Grade 3 neutropenia in subsequent cycles. 
 
Non-Hematologic Toxicities: 
- 
If Grade 1 or 2, no dose modification is required.  
- 
If Grade ≥ 3 (including, nausea, vomiting, diarrhea, and hypertension, and only if 
persisting despite optimal medical treatment), then: 
o Withhold dose of Gedatolisib and Palbociclib until toxicity is Grade ≤ 2, then 
resume treatment at next lower dose of each agent. 
o If the toxicity recurs with Grade 3 severity, withhold dose of Gedatolisib and 
Palbociclib until toxicity is Grade ≤2 and then resume treatment at the next lower 
dose of each agent or discontinue protocol directed therapy.* 
 
Gastrointestinal toxicities 
- 
If Grade 1 or 2, no dose modification is required.  
- 
If Grade ≥3 nausea/vomiting despite optimal antiemetic treatment, Grade 3 mucositis, 
or Grade 3 diarrhea despite optimal anti-diarrheal treatment, then: 
o Withhold dose of Gedatolisib and Palbociclib until toxicity is Grade ≤2, then 
resume treatment at next lower dose of each agent. 
o If the toxicity reoccurs with Grade 3 severity, despite optimal supportive care, 
withhold dose of Gedatolisib and Palbociclib until toxicity is Grade ≤ 2, and then 

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resume treatment at next lower dose of each agent or discontinue treatment at the 
discretion of the Investigator.  
o Grade 4 diarrhea/mucositis, discontinue protocol directed therapy.* 
 
Metabolic toxicities 
- 
If Grade 1, no dose modification is required.  
- 
If Grade ≥2 hyperglycemia, implement hyperglycemia management.  No dose 
modification is required.  
- 
If Grade 4 hyperglycemia despite optimal anti-hyperglycemic treatment, discontinue 
protocol directed therapy.* 
 
Pneumonitis 
- 
If Grade 1, no dose modification is required.  Initiate appropriate therapy.  
- 
If Grade 2, consider interruption of therapy with Gedatolisib and Palbociclib: 
o Initiate clinically appropriate monitoring. 
o Reduce at next lower dose of each agent. 
o If Grade ≥ 2 toxicity recurs discontinue protocol directed therapy.* 
- If Grade 3, discontinue protocol directed therapy.  
 
Failure to recover 
- 
Patients must discontinue protocol directed therapy* after failure to recover to Grade 
≤1 or baseline severity for drug-related toxicity (or, at the Investigator’s discretion, 
Grade ≤2 for toxicities not considered a safety risk for the patient) after delaying the 
initiation of the next cycle by a maximum of 2 weeks.  
 
* At discontinuation of therapy, operable patients should proceed promptly to surgery.  
 
4.6.2  Dosing Delay and Dose Modification for Adverse Events Related to Faslodex 
 
For adverse events that are possibly related to faslodex, the dose modification procedures 
stated in the Package Inserts of these drugs will be followed. 
 
4.7 Withdrawal from Study 
 
Patients are withdrawn from the study if: 
 
- 
Patients exhibit progression of disease based on radiologic and/or symptoms assessment 
- 
Unacceptable toxicity from Gedatolisib 
- 
Patient withdrawal of consent 
- 
Investigator’s discretion to withdraw patients from the study because continued 
participation in the study is not in the patient’s best interest. 
- 
Inter-current illness: a condition, injury, or disease unrelated to the intended disease for 
which the study is investigating, that renders continuing the treatment unsafe or regular 
follow-up impossible 
- 
General or specific changes in the patient's condition that renders the patient ineligible for 
further investigational treatment 

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- 
Non-compliance with investigational treatment, protocol-required evaluations or follow-up 
visits 
- 
Termination of the clinical trial by the sponsor 
 
When terminating treatment during this trial, the investigator should make every effort to 
contact the patient and to perform a final evaluation.  Also, the reason(s) for withdrawal from 
the study must be recorded. 
 
4.8 Study Procedures 
 
Table 4.8-1 (next page) provides an overview of the study procedures.  The specifics are 
described in subsequent sections. 
 
4.8.1 Screening 
 
The following procedures will be performed during patient screening, and the screening 
procedures must be performed within two weeks prior to neoadjuvant chemotherapy, except 
that radiographic tumor response assessments can be performed within 4 weeks.  The specifics 
of these tests are described in Section 4.9. 
 
- 
medical history and current medications 
- 
cancer history (date of diagnosis, current stage of disease, date of diagnosis of the current 
stage of disease, and cancer-related treatment history) 
- 
Hemoglobin A1c 
- 
ECG, assessed at baseline to exclude subjects with a marked prolongation of QT/QTc 
interval (e.g., repeated exhibition of a QTc interval >470 ms) 
- 
physical exam, body weight and height 
- 
vital signs and evaluation of symptoms 
- 
pregnancy test for women of child-bearing potential (obtain within 2 weeks prior to 
treatment initiation) (pregnancy test is also performed at least monthly in pre-menopausal 
women.) 
- 
safety assessments: 
• fasting serum glucose, fasting triglycerides, insulin, C-peptide and cholesterol.  For 
fasting serum glucose and fasting triglycerides, patients are required to fast overnight 
(nothing except water and/or medications after midnight or for a minimum of 8 hours 
before the assessment) 
• blood work (clinical chemistry, hematology and coagulation) 
- 
tumor response assessments: 
• radiographic tumor response assessments 
• clinical tumor response assessments (physical exam of the breast and axilla) 
- 
efficacy and biomarkers/genomics: 
• tumor tissues obtained via needle biopsy for pCR background information and genomics 
via the Foundation CDx™ test.  Extra tumor samples, if available, are stored for 
possible future testing. 

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• whole blood samples for assessment of genomics via the FoundationOne®Liquid test.  
Extra blood samples, if available, are stored in sample tubes from the sample kits 
provided by FoundationOne for possible future testing. 
 
4.8.2 Safety and Efficacy Assessments During and After the Study 
 
The following safety and efficacy assessments will be performed during and after the study: 
 
- 
physical exam, body weight, vital signs and evaluation of symptoms will be performed 
immediately before Gedatolisib administration.  They can be performed whenever 
clinically indicated. 
- 
vital signs and evaluation of symptoms will be performed immediately after Gedatolisib 
administration.  They can be performed whenever clinically indicated. 
- 
blood work (clinical chemistry, hematology and coagulation), as well as insulin, C-peptide 
and cholesterol are assessed in the clinic.  Blood work will be performed at baseline, 
weekly and before surgery.  During neoadjuvant therapy, blood work is to be performed 
with results available for review within 72 hours prior to the start of treatment each week.  
Insulin, C-peptide and cholesterol, as well as hemoglobin A1c are performed at baseline 
and before surgery. 
- 
efficacy and biomarkers/genomics: 
• Tumor tissues are obtained post-treatment from tumor excision surgery to assess pCR 
and genomics via the Foundation CDx™ test.  Extra tumor samples, if available, are 
stored for possible future testing 
• Whole blood samples are obtained post-treatment (before tumor excision surgery) and at 
the first follow up visit after surgery for assessment of genomics via the 
FoundationOne®Liquid test.  Extra blood samples, if available, are stored in sample 
tubes from the sample kits provided by FoundationOne for possible future testing 
 

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Table 4.8-1:  Procedures for Treatment with Gedatolisib, Palbociclib and Faslodex in Each of the Four 4-Week Treatment Cycles 
Treatments and Assessments 
Screeningb
Each 4-Week Treatment Cycle 
Surgery l 
 
Days on Week 1 
Days on Week 2 
Days on Week 3 
Days on Week 4 
 
1
2
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
7 
Treatments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gedatolisib 
 
√
 
 
 
 
 
 
√
 
 
 
 
 
 
√ 
 
 
 
 
 
 
√ 
 
 
 
 
 
 
 
Palbociclib 
 
√
√
√
√ 
√
√ 
√ 
√ 
√ 
√
√ 
√ 
√ 
√ 
√ 
√ 
√
√ 
√
√ 
√ 
 
 
 
 
 
 
 
 
Faslodex 
 
√
 
 
 
 
 
 
 
 
 
 
 
 
 
√a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Zoladex, Eligard or Lupron Depot (pre-menopausal patients 
only) 
Once every 28 days, starting 1 week prior to treatment. 
 
Medical history & current medication 
√
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer history c 
√
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A1c 
√
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√k 
ECG 
√ i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam and body weight 
√ d 
√ d
 
 
 
 
 
 √ d
 
 
 
 
 
 √ d
 
 
 
 
 
 √ d
 
 
 
 
 
 
 
Vital signs and evaluation of symptoms 
√ e 
√ e
 
 
 
 
 
 
√ e
 
 
 
 
 
 
√ e
 
 
 
 
 
 
√ e
 
 
 
 
 
 
√k 
Pregnancy test for woman of child-bearing potential 
√f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Fasting serum glucose and fasting triglycerides, as well as 
insulin, C-peptide and cholesterol 
√ g 
√ g
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√k 
- Clinical chemistry, hematology & coagulation 
√ g 
√ g
 
 
 
 
 
 √ g
 
 
 
 
 
 √ g
 
 
 
 
 
 √ g
 
 
 
 
 
 
√k 
Tumor Response Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Radiographic tumor response assessments 
√ m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ m 
- Clinical tumor response assessments 
√ n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 √ n
 
Efficacy and Biomarkers/Genomics: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Tumor Tissues:  pCR/pCR background information and 
Foundation CDx™ 
√ h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ h 
- Blood:  FoundationOne®Liquid 
√ j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ j 
pCR = pathological complete response. 
a Dosing on Days 1 and 15 takes places only in Cycle 1.  Dosing in the remaining three 4-week cycles takes place on Day 1 only. 
b Screening includes medical history; current medications; cancer history; physical exam; body weight; height (screening only); vital signs; evaluation of symptoms; and blood work (clinical 
chemistry, hematology and coagulation).  Screening must be performed within two weeks prior to neoadjuvant treatment, except that radiographic tumor response assessments can be performed 
within 4 weeks prior to neoadjuvant treatment. 
c Cancer history includes: date of diagnosis, current stage of disease, date of diagnosis of the current stage of disease, and cancer-related treatment history. 
d Physical exam and body weight will be performed during screening and immediately before Gedatolisib administration.  They can be performed whenever clinically indicated.  Height will also be 
assessed during screening. 
e Vital signs and evaluation of symptoms will be performed during screening, immediately before Gedatolisib administration, and immediately after Gedatolisib administration.  They can also be 
performed whenever clinically indicated. 
f Obtain within 2 weeks prior to treatment initiation.  Also performed at least monthly in pre-menopausal women. 
g Blood work (clinical chemistry, hematology and coagulation), as well as fasting serum glucose, fasting triglycerides, insulin, C-peptide and cholesterol are assessed in the clinic.  Blood work will 
be performed at baseline, weekly and before surgery.  During neoadjuvant therapy, blood work is to be performed with results available for review within 72 hours prior to the start of treatment 
each week.  Fasting serum glucose is performed at baseline and on Day 1 of each of the four treatment cycles during neoadjuvant therapy; fasting triglycerides are performed at baseline; whereas 
insulin, C-peptide and cholesterol are performed at baseline and before surgery.  For fasting serum glucose and fasting triglycerides, patients are required to fast overnight (nothing except water 
and/or medications after midnight or for a minimum of 8 hours before the assessment).  For tests that are required before the first dose of Cycle 1, the results from screening can be used. 

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h Tumor tissues are obtained at baseline via needle biopsy and post-treatment from tumor excision surgery to assess pCR (pCR background information at baseline) and genomics via the Foundation 
CDx™ test.  Extra tumor samples, if available, are stored for possible future testing. 
i ECG is assessed at screening to exclude subjects was a marked prolongation of QT/QTc interval (e.g., repeated exhibition of a QTc interval >470 ms). 
j Whole blood samples are obtained at baseline, post-treatment (before tumor excision surgery), and at the first follow up visit after surgery for assessment of genomics via the 
FoundationOne®Liquid test.  Extra blood samples, if available, are stored in sample tubes from the sample kits provided by FoundationOne for possible future testing. 
k To be performed before surgery to ensure vital signs, symptoms and clinical lab values are back to normal prior to surgery.  Surgery can be performed with total WBC >3,000 cells/mm3. 
l Surgery should be performed 3 weeks after completion of neoadjuvant therapy.  If surgery is delayed, the actual time of surgery in reference to completion of neoadjuvant therapy is to be recorded 
and the reason for delay (e.g., recovery from adverse effects from neoadjuvant therapy) should be documented. 
m Radiographic tumor response assessments are performed at baseline, and after 2 cycles of neoadjuvant therapy (performed on Week 4 of Cycle 2 after completion of study drug administration) 
using the same imaging modality used to obtain baseline tumor measurements.  If there is radiological evidence of disease progression, patients should be withdrawn from study and operable 
patients should proceed promptly to surgery. 
 n Clinical tumor response assessments with physical exam of the breast and axilla are performed at baseline, and at the end of each cycle during Week 4 or on Day 1 prior to the start of treatment of 
the next cycle .  Patients with Stage II-III disease who demonstrate clinical evidence of disease progression should be withdrawn from study and operable patients should proceed promptly to 
surgery. 
  

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4.9 Specifics of Tests Performed During the Study 
 
4.9.1 Safety 
 
Fasting Serum Glucose, Fasting Triglycerides, Insulin, C-Peptide and Cholesterol 
 
Fasting serum glucose will be assessed in the clinic at baseline and on Day 1 of each of the 
four treatment cycles during neoadjuvant therapy.  Fasting triglycerides will be assessed in 
the clinic at baseline.  Patients are required to fast overnight (nothing except water and/or 
medications after midnight or for a minimum of 8 hours before the assessment).  Insulin, C-
peptide and cholesterol will be assessed in the clinic at baseline and before surgery.  For the 
first day of the first week of Cycle 1, the results from screening can be used. 
 
Clinical Chemistry 
 
Clinical chemistry will be assessed at baseline, weekly on the first day of each week of the 
four 4-week treatment cycles, and before surgery.  During neoadjuvant therapy, clinical 
chemistry is to be performed with results available for review within 72 hours prior to the 
start of treatment each week.  For the first day of the first week of Cycle 1, the results from 
screening can be used.  Clinical chemistry includes: 
 
creatinine 
PO4 
total protein 
uric acid 
albumin 
blood urea nitrogen (BUN) 
Na+ 
AST/serum glutamic-oxaloacetic transaminase (SGOT) 
K+ 
ALT/serum glutamic-pyruvic transaminase (SGPT) 
Cl- 
alkaline phosphatase (ALP) 
Mg 
lactate dehydrogenase (LDH) 
Ca+2 
total bilirubin 
 
Hematology 
 
Hematology will be assessed at baseline, weekly on the first day of each week of the four 4-
week treatment cycles, and before surgery.  During neoadjuvant therapy, hematology is to be 
performed with results available for review within 72 hours prior to the start of treatment 
each week.  For the first day of the first week of Cycle 1, the results from screening can be 
used.  Hematology includes: 
 
complete blood count 
hemoglobin 
differential count 
hematocrit 
platelet count 
 
 
Coagulation will be assessed at baseline, weekly on the first day of each week of the four 4-
week treatment cycles, and before surgery.  During neoadjuvant therapy, coagulation is to be 
performed with results available for review within 72 hours prior to the start of treatment 
each week.  For the first day of the first week of Cycle 1, the results from screening can be 

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used.  Coagulation includes: 
 
INR 
Partial thromboplastin time 
 
4.9.2 Tumor Response Assessments 
 
Radiographic Tumor Response Assessments 
 
Radiographic tumor response assessments are performed at baseline (within 4 weeks prior to 
neoadjuvant therapy), and after 2 cycles of neoadjuvant therapy (performed on Week 4 of 
Cycle 2 after completion of study drug administration) using the same imaging modality used 
to obtain baseline tumor measurements.  If there is radiological evidence of disease 
progression, patients should be withdrawn from study and operable patients should proceed 
promptly to surgery. 
 
Clinical Tumor Response Assessments 
 
Clinical tumor response assessments with physical exam of the breast and axilla are 
performed at baseline, and at the end of each cycle during Week 4 or on Day 1 prior to the 
start of treatment of the next cycle.  Patients with Stage II-III disease who demonstrate 
clinical evidence of disease progression should be withdrawn from study and operable 
patients should proceed promptly to surgery. 
 
4.9.3 Efficacy and Biomarkers/Genomics 
 
Pathological Complete Response (pCR) (and pCR Background Information at Baseline) 
 
Tumor tissues will be obtained to assess pCR background information at baseline and pCR 
post-treatment from tumor excision surgery.  The definition of pCR is the absence of residual 
invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected 
breast specimen and all sampled regional lymph nodes following completion of neoadjuvant 
systemic therapy (i.e., ypT0 ypN0 in the current American Joint Committee on Cancer 
[AJCC] staging system).  The definition of pCR background information is hematoxylin and 
eosin evaluation of the breast specimen obtained via needle biopsy obtained at baseline.  
 
pCR rate will be used as an indication of treatment response to the investigational 
neoadjuvant therapy.  The endpoint of pCR in neoadjuvant therapy in breast cancer has been 
shown to correlate with drug effectiveness and OS advantage.  The FDA accepts pCR as a 
clinical endpoint for drug development and product approval (FDA Guidance for Industry 
2014).   
 
Foundation CDx™ Test on Tumor Tissues 
 
Genomics of tumor tissues are assessed using the Foundation CDx test.  Detailed information 
of this test can be obtained from the FoundationOne website:  
https://www.foundationmedicine.com/genomic-testing/foundation-one-cdx.  Briefly, 

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FoundationOne CDx is the first FDA-approved broad companion diagnostic (CDx) test that 
is clinically and analytically validated for solid tumors.  The test is designed to provide 
physicians with clinically actionable information - both to consider appropriate therapies for 
patients and understand results with evidence of resistance - based on the individual genomic 
profile of each patient’s cancer.  Every test result includes microsatellite instability (MSI) 
and tumor mutational burden (TMB) to help inform immunotherapy decisions. 
 
The sampling and shipment procedures are provided in Appendix A.  Contact information for 
ordering the sample kits is also included.  Investigators should order the sample kits at least 
3-5 days in advance to allow sufficient time for delivery of the sample kits from 
FoundationOne to the study site. 
 
FoundationOne®Liquid Test on Whole Blood 
 
In all 3 parts of the study, genomic test on liquid biopsy for solid tumors that analyze 
circulating tumor DNA in blood are assessed via the FoundationOne®Liquid test. 
 
The sampling and shipment procedures are provided in Appendix B.  Contact information for 
ordering the sample kits is also included.  Investigators should order the sample kits at least 
3-5 days in advance to allow sufficient time for delivery of the sample kits from 
FoundationOne to the study site. 
 
4.10 Surgery for Breast Cancer After Neoadjuvant Therapy 
 
Tumor excision surgery will be performed three weeks after the four treatment cycles of 
neoadjuvant therapy, or until vital signs, symptoms and clinical lab values return to normal.  
Surgery can be performed with total WBC >3,000 cells/mm3 or 3.5 bil/L.  If surgery is 
delayed, the actual time of surgery in reference to completion of neoadjuvant therapy is to be 
recorded and the reason for delay (e.g., recovery from adverse effects from neoadjuvant 
therapy) should be documented. 
 
Patients should receive the standard of care following neoadjuvant chemotherapy and surgery, 
including hormonal therapy for a minimum of five years, chemotherapy and radiation therapy 
if indicated. 
 
When surgery is performed three weeks after the four treatment cycles, the time between the 
last doses of various drugs and surgery would be as listed below: 
 
- 
seven weeks minus one day after the last dose of Faslodex 
- 
four weeks after the last dose of Palbociclib 
- 
four weeks minus one day after the last dose of Gedatolisib 
 
The type of tumor excision surgical procedures (e.g., lumpectomy or breast conserving 
surgery; partial or segmental mastectomy or quadrantectomy; simple or total mastectomy; 
radical mastectomy; modified radical mastectomy, etc.) considered to be the most appropriate 
for the study subjects will be determined by the surgeon.  Any complication, and the nature of 
complication, during surgery should be documented for potential correlation with neoadjuvant 

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therapy. 
 
4.11 Statistical Analysis 
 
This is a dose-escalation Phase Ib study with the primary objectives of assessing the safety, 
tolerability and MTD of Gedatolisib when used in combination with palbociclib and Faslodex 
in the neoadjuvant setting in previously untreated patients with ER+/HER2- breast cancer.  The 
secondary objective is to assess pCR induced by the combination of Gedatolisib, palbociclib 
and Faslodex in these patients.  Exploratory objectives include assessments of baseline values, 
and potential correlations between the baseline values and their response to the investigational 
neoadjuvant therapy, of the genomic test Foundation CDx™ in tumor tissue and the genomic 
test FoundationOne®Liquid in peripheral whole blood. 
 
Due to the small sample size of 3-6 patients per cohort with expansion of the MTD cohort to a 
total of 18 patients in this trial in this dose-escalation trial, outcome from any statistical 
analysis will not be reliable.  As such, the analyses of the results from this trial will be 
primarily descriptive. 
 
Safety and toxicities for the 18 patients in this trial will be assessed by examining each adverse 
event by grade. 
 
For the assessment of pCR, the portion of patients who achieve pCR will be presented.   
Presentation of pCR rate data will include mean and 95% confidence intervals. 
 
For the assessments of genomic results from Foundation CDx™ on tumor tissues and 
FoundationOne®Liquid on peripheral whole blood, potential correlation of treatment response 
to these parameters will be evaluated. 

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5.  GUIDELINES FOR INVESTIGATORS 
 
Guideline information related to Gedatolisib for investigators is summarized below.  Detailed 
information can be obtained from the Investigator’s Brochure. 
 
5.1 Contraindications 
 
There are no specific contraindications for Gedatolisib. 
 
5.2 Special Warnings and Precautions for Use 
 
5.2.1 Mucosal Inflammation and Stomatitis 
 
Mucosal inflammation and stomatitis have been reported in patients treated with Gedatolisib 
alone, and when used in combination with irinotecan, PD-0325901 (a MAPK/ERK kinase 
[MEK] inhibitor), docetaxel, cisplatin, or dacomitinib. 
 
Investigators should employ prophylactic measures and treatment options to reduce the 
incidence and severity of oral complications.  Severe oral toxicities can compromise the 
delivery of an adequate dose intensity of the planned cancer treatment, due to dose reduction or 
treatment schedule modifications necessary to allow for resolution of oral lesions.  Reduced 
dose intensities may potentially reduce the antitumor efficacy of the anticancer treatment. 
 
Management of oral complications of Gedatolisib includes identification of high-risk 
populations, patient education, initiation of pretreatment interventions, and timely management 
of lesions. 
 
Assessment of oral status before treatment with Gedatolisib is critical to overall patient care.  
Care should be both preventive and therapeutic to minimize risk for oral and associated 
systemic complications. 
 
Specific recommendations for minimizing oral mucosal inflammation (stomatitis) include the 
following: 
 
• Good oral hygiene (i.e., thorough and frequent cleaning of the oral cavity) 
• Avoidance of spicy, acidic, hard, and hot foods and beverages 
• Use of mild-flavored toothpastes 
• Use of saline-peroxide mouthwashes 3 or 4 times per day 
 
Specific recommendations for managing mucositis include the following: 
 
• Bland rinses: 
- 0.9% saline solution; 
- Sodium bicarbonate solution; 
- 0.9% saline/sodium bicarbonate solution. 
• Topical anesthetics: 

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- Lidocaine: viscous, ointments, sprays 
- Benzocaine: sprays, gels 
- 0.5% or 1.0% dyclonine hydrochloride 
- Diphenhydramine solution 
• Mucosal coating agents: 
- Aluminum hydroxide 
- Bismuth Subsalicylate 
- Hydroxypropyl methycellulose film-forming agents 
- Polyvinylpyrrolidone-sodium hyaluronate gel 
• Analgesics: 
- Benzydamine HCI topical rinse 
- Opioid drugs: oral, intravenous (e.g., bolus, continuous infusion, patient controlled 
analgesia [PCA], patches, transmucosal 
- Anti-inflammatory treatment as required 
(Nonsteroidal anti-inflammatory drugs that affect platelet adhesion and damage gastric 
mucosa are contraindicated, especially if thrombocytopenia is present.) 
• Aggressive antimicrobial treatment for any new mouth infections. 
 
For additional recommendations regarding the prevention and treatment of mucositis, refer to 
the American Society of Clinical Oncology (ASCO) guidelines (Keefe et al 2007). 
 
5.2.2 Drug-Induced Pneumonitis 
 
Drug-induced pneumonitis was not reported in clinical trials in which Gedatolisib is used 
alone.  One patient treated with Gedatolisib in combination with dacomitinib experienced 
Grade 3 drug-induced pneumonitis.  The investigator considered the event to be related to 
dacomitinib and not Gedatolisib.  No other Gedatolisib-treated patients experienced drug-
induced pneumonitis. 
 
Drugs which are mTOR inhibitors are known to be associated with pulmonary toxicity.  Drug-
induced pneumonitis was reported observed in patients treated with temsirolimus (Duran et. al. 
2006).  Approximately 50% of patients were symptomatic, and dyspnea and dry cough were 
the most frequently observed symptoms.  Two different radiological patterns were described, 
including ground glass opacities and lung parenchymal consolidation.  The management of this 
toxicity was variable, ranging from no intervention, corticosteroid treatment to discontinuation 
of the drug.  The presentation and its severity are also variable. 
 
Monitoring for drug-induced pneumonitis, and other respiratory events, is recommended.  The 
risk of developing this toxicity may be increased among subjects with abnormal pretreatment 
pulmonary functions or history of lung disease. 
 
5.2.3 Nausea and Vomiting 
 
Nausea and vomiting have been reported in patients treated with Gedatolisib alone, and when 
Gedatolisib is used in combination with irinotecan, PD-0325901, docetaxel, cisplatin, or 
dacomitinib. 

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The routine prophylactic use of antiemetic medications is not recommended up to the first 
observation of Grade ≥2 nausea and/or vomiting.  Once the patient's sensitivity to the 
emetogenic activity of Gedatolisib or Gedatolisib -based regimen is identified, the most 
appropriate antiemetic prophylaxis should be adopted.  The drug regimen for antiemetic 
prophylaxis and treatment should be selected according to the Investigator's clinical judgment 
and experience. 
 
5.2.4 Diarrhea 
 
Diarrhea has been reported in patients treated with Gedatolisib alone, and when Gedatolisib is 
used in combination with irinotecan, FOLFIRI, PD-0325901, docetaxel, cisplatin, or 
dacomitinib. 
 
Anti-diarrheal measures should be started at the earliest sign of any of the following: 
 
• 
Poorly formed or loose stool 
• 
Occurrence of 1 or 2 more bowel movements than usual in 1 day 
• 
Significant increase in stool volume or decreased fecal consistency 
 
Patients should be instructed to refer immediately to the site in case of these symptoms.  The 
regimen for anti-diarrheal treatment will be at the discretion of the Investigator. 
 
5.2.5 Asthenia and Fatigue 
 
Asthenia and/or fatigue have been reported in patients treated with Gedatolisib alone, and 
when Gedatolisib is used in combination with irinotecan, FOLFIRI, PD-0325901, docetaxel, 
cisplatin, or dacomitinib. 
 
Fatigue is common in patients with cancer and the correction of potential co-morbidities (e.g., 
anemia, electrolyte imbalances, and depression) may be a useful approach to limit the severity 
of the event.  Approaches to the diagnosis and the management of cancer-related fatigue are 
discussed in the National Comprehensive Cancer Network Guideline for Cancer Related 
Fatigue. 
 
5.2.6 Hyperglycemia 
 
Hyperglycemia, as a laboratory abnormality, has been reported in patients treated with 
Gedatolisib alone, and when Gedatolisib is used in combination with irinotecan, FOLFIRI, PD-
0325901, docetaxel, cisplatin, or dacomitinib. 
 
The PI3-K/mTOR pathway is known to be important in the maintenance of glucose 
homeostasis.  The inhibition of PI3-K/mTOR is frequently associated with hyperglycemia and 
is a known class effect.  Patients treated with Gedatolisib should be monitored for glucose 
blood levels. 
 

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The following guidelines (see Table 5.2.6-1, below) are general strategies that investigators 
may consider implementing in patients with hyperglycemia; these guidelines are not 
mandatory and are not meant to replace institutional practices. 
 
On-study hyperglycemia management: 
 
• 
If FBG ≥200 mg/dL, repeat FBG in 1 week. 
 
Table 5.2.6-1:  Guidelines for Hyperglycemia Management 
FBG 
Management¥ 
≥160 mg/dL, on 2 
readings 1 week apart 
• Patients without history of DM 
○ Lifestyle modification 
○ Initiate metformin therapy* 
○ If FBG ≥200 mg/dL, initiate home monitoring QD. 
○ If FBG >200-250 mg/dL after 2 weeks of metformin: 
▪ Continue metformin and add sulfonylurea ¥,** 
○ If FBG ≥250 mg/dL after 1 week 
▪ Add sulfonylurea** or 
▪ Add insulin and titrate to maintain FBG <200 mg/dL 
Targets of treatment 
- Fasting / AC (before meal) glucose:  <160 mg/dL 
- Random glucose:  <200 mg/dL 
- Avoid hypoglycemia 
• Patients with history of DM 
○ Titrate current medications to maintain FBG <200 mg/dL 
○ Consult with endocrinologist/primary care physician who is following DM 
Symptomatic§ Grade 3 
(250-500 mg/dL) 
• IV fluids and consider hospitalization 
• Consider holding PI3-K inhibitor dose until ≤Grade 2 or baseline and then restarting at 
original dose level 
Grade 4 
• IV fluids and consider hospitalization 
• Consider holding PI3-K inhibitor dose until ≤Grade 2 or baseline and then restarting at 1 
lower dose level 
Grade 4 despite 
optimal anti-
hyperglycemic therapy 
• IV fluids and consider hospitalization 
• Discontinue treatment 
AC = ante clbum (before meals); DM = Diabetes Mellitus; FBG = fasting blood glucose; IV = intravenous or 
intravenously; QD = once daily 
* 
Contraindicated in patients with renal insufficiency 
¥ 
Discontinue oral hypoglycemic agents and monitor for hypoglycemia when PF-05212384 is interrupted for lengthy periods 
or is discontinued 
** Can also use meglitinide-class drugs, especially short acting agents (e.g., repaglinide) 
§ 
Symptoms such as, but not limited to hypotension, severe dehydration, severe metabolic abnormalities manifested as ECG 
changes 
 
 
5.2.7 Decreased Appetite 
 
Decreased appetite has been reported in patients treated with Gedatolisib alone, and when 
Gedatolisib is used in combination with irinotecan, PD-0325901, cisplatin, or dacomitinib. 
 

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Similar to fatigue, decreased appetite is a multi-factorial condition in patients with cancer.  
Treatment of potentially reversible complications such as infection, uncontrolled pain, or 
depression may be useful to mitigate the severity of decreased appetite. 
 
5.2.8 Skin Effects 
 
Skin effects have been reported in patients treated with Gedatolisib alone, and when 
Gedatolisib is used in combination with irinotecan, FOLFIRI, PD-0325901, docetaxel, 
cisplatin, or dacomitinib.  The reported skin effects include:  dry skin, acneiform dermatitis, 
palmar-plantar erythrodysaesthesia syndrome, pruritus, rash (generalized rash, rash 
erythematous, rash maculopapular, rash macular, rash papular, skin exfoliation, and catheter 
site rash), skin infection, skin lesion, skin fissures, skin inflammation, eczema, erythema, 
catheter site erythema, and cellulitis. 
 
Patients should be informed about the frequent related cutaneous adverse reactions associated 
with Gedatolisib and the need to avoid exposure to extreme temperatures, the use of lotions 
(since lotions can contain alcohol) and direct sunlight (or tanning beds).  The use of preventive 
topical treatments, such as bathing techniques using bath oils or mild moisturizing soaps and 
bathing in tepid water may help to prevent the appearance of cutaneous toxicity or reduce its 
intensity.  The use of regular moisturizing creams is also recommended to keep an appropriate 
skin hydration and humidity, which is useful to reduce the symptoms in case of rash 
appearance. 
 
5.2.9 Hematological Abnormalities 
 
Hematological abnormalities have been reported in patients treated with Gedatolisib alone, and 
when Gedatolisib is used in combination with irinotecan, PD-0325901, docetaxel, cisplatin, or 
dacomitinib.  Examples of hematological abnormalities include:  anemia, lymphopenia, white 
blood cell decrease, neutrophil count decrease 
 
Anemia, although of multifactorial etiology in patients with advanced cancer, is probably 
related to the role of the PI3-K/mTOR pathway in the expansion of erythroid progenitors 
(Bakker et. al., 2004) and inhibition of this pathway by PF-05212384.  Lymphopenia is likely 
secondary to the inhibition of the PI3-K isoforms gamma and delta, which play an essential 
role in lymphocyte development and differentiation (Ghigo et. al., 20 10). 
 
As of 29 May 2014, no clinical implications, e.g., opportunistic infections, for treatment 
related lymphopenia have been observed.  Therefore there are no specific recommendations for 
management of lymphopenia.  However, considering the role of the PI3-K/mTOR pathway in 
the bone marrow physiology, Gedatolisib should be administered with caution to patients with 
abnormal blood counts and complete blood counts (CBC) should be monitored following 
treatment with Gedatolisib. 
 

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5.2.10 Elevation of Liver Enzymes 
 
Elevation of liver enzymes (ALT, AST, bilirubin, and/or alkaline phosphatase), as laboratory 
abnormalities, have been reported in patients treated with Gedatolisib alone, and when 
Gedatolisib is used in combination with irinotecan, PD-0325901, docetaxel, cisplatin, or 
dacomitinib. 
 
In most cases, the transaminase values returned to baseline value after treatment interruption.  
The elevated alkaline phosphatase and bilirubin were not reported as AEs and likely related to 
progression of the underlying malignancy. 
 
Only patients with non-clinically significant alterations of liver function should receive 
Gedatolisib.  Additionally, patients being treated with Gedatolisib should be routinely 
monitored for elevation of liver enzymes. 
 
5.2.11 Use in Patients with Renal Impairment 
 
Elevations of creatinine, as laboratory abnormalities, have been reported in patients treated 
with Gedatolisib alone, and when Gedatolisib is used in combination with irinotecan, PD-
0325901, docetaxel, cisplatin, or dacomitinib. 
 
The mild renal toxicity associated with PF-05212384 may be related to the physiological role 
of the PI3-K/mTOR pathway in the tubular and glomerular cell physiology. 
 
Only patients with non-clinically significant alterations of kidney function should receive 
Gedatolisib.  Careful attention should be paid to concomitant clinical situations which may 
impair renal function (e.g., dehydration) as well as concomitant nephrotoxic medications. 
 
5.3 Interaction with Other Medicinal Products and other Forms of Interaction 
 
No clinical information is currently available regarding the potential for drug-drug interactions 
with Gedatolisib and co-administrated drugs. 
 
5.4 Fertility, Pregnancy, and Lactation 
 
Gedatolisib was assessed in a series of genetic toxicology assays consisting of the microbial 
reverse mutation, in vitro cytogenetic (human lymphocyte), and in vivo rat micronucleus 
assays.  All in vitro tests were conducted with and without exogenous metabolic activation 
using concentrations up to those limited by cytotoxicity or insolubility. 
 
Gedatolisib was not genotoxic in either in vitro or in vivo assays.  Gedatolisib has not been 
tested for carcinogenic activity in a lifetime rodent bioassay. 
 
Safety for women of child-bearing capacity cannot be implied from the existing data.  Women 
of child-bearing potential (not surgically sterile or postmenopausal) must use effective 
contraception while receiving trial treatment and for three months thereafter.  Women of child-

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bearing potential should also have a negative pregnancy test prior to treatment with 
Gedatolisib. 
 
No studies have been conducted in humans to assess the impact of Gedatolisib on milk 
production, its presence in breast milk and its effects on the breast-fed child.  Since drugs are 
commonly excreted in human milk, and because of the potential for serious adverse reactions 
in nursing infants, lactating female patients should not be treated with Gedatolisib. 
 
5.5 Effects on Ability to Drive and Use Machines 
 
Patients should be instructed to avoid potentially hazardous tasks such as driving or operating 
machinery if they experience dizziness following treatment with Gedatolisib. 
 
5.6 Reference Safety Information 
 
Table 5.6-1 (below) represents the adverse drug reaction observed among patients receiving 
single Gedatolisib. 
 
 
Table 5.6-1:  Summary of Adverse Drug Reactions Following IV Administration of Single Gedatolisib a 
System Organ Class 
ADR (by Preferred Term) 
Frequency (%) 
Gastrointestinal Disorders 
Nausea 
54.9 
Mucosal Inflammation 
54.9 
Vomiting 
35.4 
Diarrhea 
32.9 
Stomatitis 
15.9 
Dry Mouth 
13.4 
General Disorders and  
Administration Site Conditions 
Asthenia 
28.0 
Pyrexia 
19.5 
Fatigue 
30.5 
Hepatobiliary Disorders 
Aspartate aminotransferase increased 
13.4 
Alanine aminotransferase increased 
12.2 
Metabolism and Nutrition Disorders 
Appetite decreased 
40.2 
Hyperglycemia 
23.2 
Dehydration 
6.1 
Nervous System Disorders 
Dysgeusia 
26.8 
Skin and Subcutaneous Tissue Disorders 
Rash 
18.3 
Dry skin 
7.3 
Pruritus 
9.8 
Dermatitis acneiform 
3.7 
IV = intravenous 
a  Dose of Gedatolisib was 154 mg, given once weekly. 
 
 
5.7 Overdose 
 
No information regarding overdose of Gedatolisib in humans is available.  In the event of an 
accidental overdose, the subject should be monitored for the possible signs of toxicity as 
mentioned above.  In addition, Dr. Anthony Hoffman (or designee) should be notified.  As 

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there is no specific antidote for overdose of Gedatolisib, general supportive care should be 
provided. 
 
5.8 Drug Abuse and Dependence 
 
No data are available regarding long term administration and the potential dependence on 
Gedatolisib. 
 

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6.  ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
6.1  Adverse Events 
 
An AE is any untoward medical occurrence in a subject administered with an investigational 
product and does not necessarily have to have a causal relationship with the investigational 
product.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
lab finding), symptom or disease temporally associated with the use of the investigational 
product.  This includes worsening of a pre-existing condition or increase in frequency of a pre-
existing condition.  An AE is considered serious if it meets the serious criteria described in 
Section 6.3 (below).  To avoid confusion or misunderstanding of the difference between 
“serious” and “severe”, which are not synonymous, the following clarification is provided: 
 
The term “severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache).  This is not the same as 
“serious”, which is based on patient/event outcome or action criteria usually associated 
with events that pose a threat to a patient’s life or functioning.  Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations.   
 
Adverse drug reactions (ADRs) are all noxious and unintended responses to a medicinal 
product related to any dose that a causal relationship between the medicinal product and an AE 
is at least a reasonable possibility (i.e., the relationship cannot be ruled out).  An unexpected 
ADR is any adverse reaction not consistent with the specificity and severity as that described 
in the latest Investigator’s Brochure or the clinical protocol.  
 
6.2  Adverse Event Grading, Recording and Reporting 
 
The physician or designee is to question the patient about AEs and intercurrent illnesses since 
the last assessment and is to record the information in the subjects’ medical record.  The 
questioning of subjects regarding AE is generalized such as, “How have you been feeling since 
your last visit?”  The onset and end dates, severity, and relationship to study drug are to be 
recorded for each AE.  The severity of the AE is to be assessed and graded according the NCI 
CTC. 
 
Any lab value considered by the investigator to be clinically significant should be considered 
an AE.  However, abnormal clinical lab values of clinical significance which were present at 
baseline and did not change in severity or frequency during the investigational treatment or can 
obviously be attributed to the underlying disease will not be considered an ADR.  Significant 
abnormal values occurring during the trial will be followed until repeat test results return to 
normal, stabilize, or are no longer clinically significant. 
 
If a patient becomes pregnant while on the study, the investigational treatment will be 
immediately stopped.  The investigator is required to report the pregnancy to Dr. Anthony 
Hoffman or the designee, within 24 hours via telephone or fax.  If initially reported via 
telephone, it must be followed-up with a written report via fax within 24 hours of the telephone 

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report.  Pregnancy must be followed to term and outcome of the pregnancy must also be 
reported. 
 
All AEs will be evaluated by the investigator for potential relationship to the investigational 
treatment in the following categories:  
 
Unrelated: 
The AE is clearly not related to the investigational drug. 
Unlikely 
The AE is unlikely related to the investigational drug. 
Possibly Related 
The AE is possibly related to the investigational drug. 
Likely: 
The AE may be related to the investigational drug. 
Definitely: 
The AE is clearly related to the investigational drug. 
 
Patients who experience AEs will be monitored with clinical assessments and lab tests, as 
determined appropriate by the investigator.  All AEs are to be followed to satisfactory 
resolution or stabilization of the event(s).  Any action taken or outcome (e.g., hospitalization, 
discontinuation of therapy, etc.) as well as follow-up tests are to be recorded in the patient’s 
medical record.  Follow-up test and/or lab results are to be filed with the patient’s source 
documentation.  
 
All AEs are documented, kept as part of the patient’s medical record and recorded using AE 
Case Report Form (to be provided to the investigators).  All AEs are reported in the annual 
progress reports to Dr. Anthony Hoffman/designee, the IRB, FDA (via Dr. Anthony 
Hoffman/designee), and Pfizer, Inc. (via Dr. Anthony Hoffman/designee).  
 
6.3  Serious Adverse Events 
 
A serious adverse event (SAE) is defined as an untoward (unfavorable) medical occurrence 
that at any dose: 
 
- Results in death, 
- Is life-threatening (the term “life-threatening” refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe), 
- Requires inpatient hospitalization or prolongation of existing hospitalization, 
- Results in persistent or significant disability/incapacity, 
- Results in a congenital anomaly /birth defect, or 
- Jeopardizes the subject/patient and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
 
Important medical events that do not result in death, are not life-threatening, or do not require 
hospitalization can be considered SAEs when, based upon appropriate medical judgment, they 
jeopardize the subject or require medical or surgical intervention to prevent any of the 
outcomes listed above.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions not requiring hospitalization; or development of drug dependency or drug abuse.   
 

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6.4  Serious Adverse Event Recording and Reporting 
 
Any SAE, including death from any cause that occurs starting from the first dose of the 
investigational drug to within 30 days after stopping the study drug (regardless of relationship 
to study drug), must be recorded using the SAE Report Form (to be provided by Dr. Anthony 
Hoffman or the designee) and reported to the Medical Monitor (see front page of this protocol) 
and Dr. Anthony Hoffman/designee immediately via telephone or fax within 24 hours.  If 
initially reported via telephone, this must be followed-up with a written report via fax within 
24 hours of the telephone report.  It is important to mark on the SAE Report Form the potential 
relationship to the investigational treatment in the following categories:  
 
Unrelated: 
The SAE is clearly not related to the investigational drug. 
Unlikely 
The SAE is unlikely related to the investigational drug. 
Possibly Related 
The SAE is possibly related to the investigational drug. 
Likely: 
The SAE may be related to the investigational drug. 
Definitely: 
The SAE is clearly related to the investigational drug. 
 
Where relationship to the investigational product is uncertain or unknown (such as in the event 
of a blinded study, if applicable), the SAE must still be recorded using the SAE Report Form 
but should be marked "unknown" relationship with investigational drug.  Expected SAE (i.e., 
those described in the Investigator's Brochure) do not require expedited, but still needs to be 
captured as SAE using the SAE Report Form.  AEs that are classified as unexpected and 
serious, but are unrelated to the investigational drugs will not be reported by expedited means. 
 
Any SAE occurring at any other time after completion of the study must also be recorded using 
the SAE Report Form and must be promptly reported to IRB, Dr. Anthony Hoffman/designee, 
FDA (via Dr. Anthony Hoffman/designee), and Pfizer, Inc. (via Dr. Anthony 
Hoffman/designee), if a causal relationship to the study drug is suspected.  If initially reported 
via telephone, this must be followed-up with a written report via fax within 24 hours of the 
telephone report.   
 
The investigator (or the designee) is required to fill out the SAE Report Form.  Sufficient 
details must be provided to allow for a medical assessment of the SAE and independent 
determination of possible causality.  The investigator is obliged to pursue and provide 
additional information as requested by Dr. Anthony Hoffman, or the designee.  Follow-up 
information about a previously reported SAE must be reported within 72 hours of receipt.  
 
Dr. Anthony Hoffman (the sponsor) is required to report to the regulatory agencies, other study 
sites involved in clinical trials of Gedatolisib, and Pfizer, Inc. (the sponsor of Gedatolisib), in 
an expedited manner, all unexpected SAEs that are associated with the use of the 
investigational product.  Therefore, it is imperative that Dr. Anthony Hoffman (or the 
designee) be informed within 24 hours of any SAE (including overdose) as noted above, so 
that reporting to the regulatory agencies can be met within the required time frame.  It is the 
responsibility of the investigator to promptly notify the IRB of all AEs, SAEs and/or ADRs 
according to institutional guidelines and applicable local laws and regulations.   

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7.  COMPLIANCE, PROTOCOL AMENDMENT, AND DATA MANAGEMENT 
 
7.1  Compliance 
 
This study will be conducted according to GCP, applicable regulatory requirements and 
applicable institutional guidelines.  The investigator will conduct the study in compliance with 
the protocol and approved by the IRB unless the modification is needed to eliminate an 
immediate hazard to patients.  In this case, the IRB and FDA (via Dr. Anthony 
Hoffman/designee) must be promptly notified. 
 
Investigators are required to ensure compliance with respect to the investigational drug 
schedule, visit schedule and procedures stated in the protocol.  Appropriate written justification 
must be documented by the investigator for all inadvertent departures from protocol 
requirements. 
 
7.2  Protocol Amendments 
 
Changes to a protocol must be implemented by a formal protocol amendment.  Amendments to 
the protocol must be initiated by the sponsor of the trial.  The formal amendment must be 
signed by the principal investigator, approved by the IRB, and submitted to the regulatory 
agencies, prior to implementation.  If the change or deviation increases risk to the study 
population, or adversely affects the validity of the clinical investigation or the patient’s rights, 
full IRB approval must be obtained prior to implementation.  For changes that do not involve 
increased risk or affect the validity of the investigation or the patient’s rights, IRB approval 
may be obtained by expedited review.  A modification to the protocol may be initiated without 
IRB approval or without prior submission to the regulatory agencies ONLY when the change 
is necessary to eliminate apparent immediate hazard to the patients.  In that event, the 
investigator must notify, in writing, Dr. Anthony Hoffman/designee, the IRB, FDA (via Dr. 
Anthony Hoffman/designee), and Pfizer (Dr. Anthony Hoffman/designee). 
 
In some cases, an amendment may require a change to a consent form.  The investigator must 
receive IRB approval prior to implementing the revising informed consent.  Additionally, 
changes to the case report forms (CRFs), if required, will be incorporated in the amendment. 
 
7.3  CRFs 
 
Dr. Anthony Hoffman (or designee) will provide the study site with CRFs for each patient.  
The investigator or designee should complete the CRFs expeditiously to capture all the 
relevant information.  The investigator (or his/her designee) must also follow the instructions 
for providing signature and date, as well as in handling missing data, incorrect data entry, etc. 
 
7.4  Data Entry 
 
A Research Study Assistant (RSA) will be assigned by the principal investigator to the study at 
the study site.  The responsibilities of the RSA include project compliance, data collection, 
abstraction and entry, data reporting, regulatory monitoring, problem resolution and 

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prioritization, and coordinate the activities of the protocol study team. 
 
The data collected for this study will be entered into a secured database designed and 
maintained by Dr. Anthony Hoffman or its designee.  Source documentation must be available 
to support the computerized patient record. 
 
7.5  Record Maintenance 
 
All study records will be retained for at least 2 years after the last marketing approval, or 2 
years after discontinuation of the clinical development of the investigational drug.  In the event 
that the FDA, Health Canada, EMEA or other regulatory agencies contact the investigator for 
the purposes of an audit of the study, the investigator will notify Dr. Anthony Hoffman 
immediately. 
 
If the investigator relocates to another institution, the responsibility of keeping the study 
records must be transferred to another person at the current institution and Dr. Anthony 
Hoffman must be notified in writing if such a change should occur. 

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8.  PATIENT AND STUDY DISCONTINUATION 
 
Listed below are criteria for the discontinuation of the study.  However, patients who fail to 
return for the follow-up visits will be contacted and queried as to the reason they have failed to 
complete the study with special attention to health status. 
 
A. Patients have the right to withdraw from the study at any time for any reason. 
 
B. The investigator has the right to withdraw patients from the study according to his/her 
discretion, if the investigator determines that continued participation is not in the patient’s 
best interest.  As an excessive rate of withdrawals can render the study not interpretable, 
unnecessary withdrawal of patients should be avoided.  When a patient discontinues 
investigational treatment, the investigator should make every effort to contact the patient and 
to perform a final evaluation.  The reason(s) for withdrawal must be recorded.  Criteria for 
terminating subject's participation in the study are listed below: 
 
- Disease progression significantly greater than expected 
- Unacceptable toxicity of the investigational product 
- Patient withdrawal of consent 
- Investigator’s discretion 
- Intercurrent illness:  a condition, injury, or disease unrelated to the intended disease for 
which the study is investigating, that renders continuing the treatment unsafe or regular 
follow-up impossible 
- General or specific changes in the patient's condition that renders the patient ineligible for 
further investigational treatment 
- Non-compliance with investigational treatment, protocol-required evaluations or follow-up 
visits 
- Termination of the clinical trial by the sponsor (see below) 
 
C. Dr. Anthony Hoffman (sponsor) has the right to terminate this study at any time.  Reasons 
for terminating the study may include the following: 
 
- Patient enrollment is unsatisfactory 
- Quality or quantity of data recording is inaccurate or incomplete 
- The incidence or severity of ADRs in this or other studies indicates a potential health 
hazard to patients 
- Poor adherence to protocol and regulatory requirements 
- Plans to modify or discontinue the development of the investigational product 

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9.  REFERENCES 
 
Bakker WJ, et al. Fox03a regulates erythroid differentiation and induces BTG1, an activator of 
protein arginine methyl transferase 1. J Cell BioI. 2004;164: 175-84. 
Baselga J, Campone M, Piccart M, et al.  Everolimus in Postmenopausal Hormone-Receptor-
Positive Advanced Breast Cancer. N Engl J Med 2012; 366:520-9. 
Duran LL, et al. Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus.  
Euro J Cancer 2006;42(12):1875-80. 
Fry D W, Harvey P J, Keller P R, et al. Specific Inhibition of Cyclin-Dependent Kinase 4/6 by 
PD 0332991 and Associated Antitumor Activity in Human Tumor Xenografts. Mol Cancer 
Ther 2004; 3 1427-1438. 
Ghigo A, et al. PBK inhibition in inflammation: toward tailored therapies for specific diseases. 
Bioessays 2010;32:185-96. 
Keefe DM, et al.: Updated clinical practice guidelines for the prevention and treatment of 
mucositis. Cancer 2007;109(5):820-31. 
Mathiesen RR, Fjelldal R, Liestol K, Due EU, Geigl JB, Riethdorf S, et al.  High-resolution 
analyses of copy number changes in disseminated tumor cells of patients with breast cancer.  
Int J Cancer (2012) 131(4):E405–15. doi:10.1002/ijc.26444. 
Sweeney C, Chen Y, Carducci M A, et al. Impact on Overall Survival (OS) with hemohormonal 
Therapy Versus Hormonal Therapy for Hormone-Sensitive Newly Metastatic Prostate Cancer 
(mPrCa): An ECOG-led Phase III Randomized Trial.  J Clin Oncol 32:5s, 2014 (suppl; abstr 
LBA2). 
Turner NC, Ro J, Andre F, et al.  PALOMA3: A double-blind, phase III trial of Faslodex with or 
without palbociclib in pre- and post-menopausal women with hormone receptor-positive, 
HER2-negative metastatic breast cancer that progressed on prior endocrine therapy.  J Clin 
Oncol 33, 2015 (suppl; abstr LBA502). 

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APPENDICES 

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Appendix D: Sampling and Shipment Procedures for FoundationOne CDx 
  

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Appendix B: Sampling and Shipment Procedures for FoundationOne®Liquid