Clinical trial NCT02920450
Conditions: Non-Small Cell Lung Cancer
Keywords: lung carcinoma
Sponsor: University of Florida
Start date: 2017-09-25; Completion date: 2019-04-04
Enrollment: 3 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this research study is to determine if the study drug, Gedatolisib (PF-05212384), given in combination with paclitaxel and carboplatin will work against unresectable non-small cell lung cancer.

Detailed description:
Approximately 70% of patients with unresectable non-small cell lung cancer (NSCLC) who receive and progress through frontline chemotherapy will be eligible for second line treatments. Any of the agents which are available for frontline therapy can be used in the salvage setting, though only erlotinib, docetaxel, and pemetrexed (in non-squamous cell carcinoma) are FDA-approved in the salvage setting based upon their demonstrated survival benefit in randomized phase III trials. All three appear to be roughly equivalent in terms of clinical benefit, which is admittedly modest, with response rates \<10%, clinical benefit rates of approximately 50%, and overall survivals of approximately 6 months. Still, a substantial number of patients may not benefit from the agents in the salvage treatment setting, thus it is critical to identify those patients who stand to benefit the most.

The study will consist of two phases, Ib and II. The phase Ib portion will study dose escalations in separate 3+3 cohorts using escalating doses of PF-05212384. The phase II portion will consist of a two stage Simon design. The doses for paclitaxel (200 mg/m2, Q21 days) and carboplatin (AUC=6, Q21 days) do not adjust as part of the study design. The dose of PF-05212384 will be determined during the Phase Ib portion.

The primary endpoint of the phase Ib portion of this protocol is to determine a tolerable phase II dose of PF-05212384 in combination with paclitaxel and carboplatin. The primary endpoint of the phase II portion of this study is to determine the objective response rate of disease to the administration of PF-05212384 in combination with paclitaxel and carboplatin. A secondary endpoint of this study will be progression-free survival following PF-05212384 therapy.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Gedatolisib intervention 2: Paclitaxel intervention 3: Carboplatin
Intervention descriptions: intervention 1: During the first phase, subjects will be sequentially enrolled to each increasing dose level, beginning with dose level 1 (110 mg) until the first dose limiting toxicity occurs, or safely accrued to dose level 3. PF-05212384 is intravenously infused over a thirty minute period. The dose given in the phase 2 portion will be the MTD determined in the phase Ib portion of the study.

Dose Level 1: 110 mg Dose Level 2: 150 mg Dose Level 3: 180 mg intervention 2: Given as 200 mg/m2 infusion over a three hour period at every twenty-one days; the dose will not adjust as part of the study design. intervention 3: The carboplatin dose (mg) = AUC x (CrCl + 25) where AUC = 6 depending on the dose level. carboplatin is intravenously infused over a thirty minute period following paclitaxel administration; the dose will not adjust as part of the study design.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A NON-RANDOMIZED PHASE IB-II PROTOCOL OF  
PACLITAXEL, CARBOPLATIN AND THE DUAL PI3K/MTOR KINASE INHIBITOR, 
PF-05212384 (GEDATOLISIB), FOR PATIENTS WITH ADVANCED OR 
METASTATIC NON-SMALL CELL CARCINOMA OF THE LUNG 
 
Protocol Number: 
 
 
UF-STO-LUNG-002  
 
Coordinating Center: 
 
University of Florida 
 
Principal Investigator:  
 
Dennie Jones, MD 
 
 
1601 SW Archer Road 
 
 
Gainesville, FL  32608-1135 
 
 
Telephone: 352-548-6000, ext. 4320 
 
 
Fax:  352-548-6463 
 
 
E-mail address:   Dennie.Jones@medicine.ufl.edu  
 
 
 
 
 
 
 
Dennie.Jones@VA.gov 
 
Co-Investigators: 
Fred Kaye, MD   
 
 
 
 
Jennifer Duff, MD  
 
 
 
 
 
 
David DeRemer, PharmD 
                                                            
 
Statistician:  
 
 
Susan McGorray, PhD 
 
Protocol Managers:   
 
Allison Allegra, MPH 
                                                            Alisha Daniels, MD 
 
Clinical Phase: 
 
 
Phase I-II 
 
IND Status:  
 
 
IND 132757 
 
Investigational Agent: 
 
Gedatolisib 
 
 
 
Date of Original Protocol:  
June 22, 2016 
 
Date of Current Protocol:  
January 10, 2019 
 
Version of Current Protocol: 
Version 1.9 
 
 
 
 
 


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CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless 
law or regulations require such disclosure.  Persons to whom the information is disclosed 
must be informed that the information is confidential and may not be further disclosed by 
them 
 
 
ABBREVIATIONS ................................................................................................................................. 5 
PROTOCOL SIGNATURE PAGE ...................................................................................................... 8 
PROTOCOL SYNOPSIS ....................................................................................................................... 9 
1.0 
BACKGROUND .................................................................................................................................... 16 
1.1 
Lung Cancer Therapy ......................................................................................................... 16 
1.2 
PI3K/mTOR Signaling ....................................................................................................... 16 
1.3 
PF-05212384 .......................................................................................................................... 17 
1.3.1 
Nonclinical Toxicity ...................................................................................................... 18 
1.3.2 
Nonclinical Safety Pharmacology ............................................................................ 19 
1.3.3 
Nonclinical Pharmacology .......................................................................................... 19 
1.4 
Effects in Humans ................................................................................................................ 25 
1.4.1 
Pharmacokinetics and Product Metabolism in Humans ........................ 29 
1.4.2 
Bioavailability ............................................................................................................... 29 
1.4.3 
Pharmacokinetics in Patients ............................................................................... 30 
1.4.4 
Drug-Drug Interactions ............................................................................................ 30 
1.4.5 
Safety ................................................................................................................................. 30 
1.4.6 
QTc Prolongation ........................................................................................................ 39 
1.4.7 
Efficacy .............................................................................................................................. 41 
1.5 
CARBOPLATIN (CBDCA) (NSC-241240) .................................................................... 42 
1.5.1 
Description ..................................................................................................................... 42 
1.5.2 
Toxicology ....................................................................................................................... 42 
1.5.3 
Pharmacology ............................................................................................................... 42 
1.6 
PACLITAXEL, Taxol® (NSC-673089) .......................................................................... 43 
1.6.1 
Description ..................................................................................................................... 43 
1.6.2 
Toxicology ....................................................................................................................... 43 
1.6.3 
Pharmacology ............................................................................................................... 44 
2. 
STUDY POPULATION .......................................................................................................................... 45 
2.1 
Inclusion Criteria ................................................................................................................. 45 
2.2 
Exclusion Criteria ................................................................................................................ 46 
2.3 
Inclusion of Women and Minorities ........................................................................... 47 
3. 
REGISTRATION PROCEDURES ....................................................................................................... 47 
4. 
STUDY TREATMENT............................................................................................................................ 47 
4.1 
Treatment Schedule/Administration ....................................................................... 47 
4.2 
Overall Treatment Plan .................................................................................................... 48 
4.3 
Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD) ...... 50 
4.4 
Chemotherapy Guidelines ............................................................................................... 50 


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4.5 
Concomitant Therapy ........................................................................................................ 51 
4.5.1 
Allowed Concomitant Therapy ............................................................................ 51 
4.5.2 
Prohibited Concomitant Therapy ....................................................................... 52 
4.6 
Dose Modifications .............................................................................................................. 52 
4.6.1 
Dose Modification Table .......................................................................................... 52 
4.6.2 
Non- Hematologic Toxicity ..................................................................................... 53 
4.6.3 
Hematologic Toxicity ................................................................................................ 54 
4.7 
Supportive Care Guidelines ............................................................................................ 54 
4.7.1 
Special Warnings and Precautions for Use .......................................................... 54 
5. 
TREATMENT DISCONTINUATION ............................................................................................... 55 
5.1 
Removal of Subjects From Study ................................................................................. 55 
5.2 
Criteria For Study Treatment Discontinuation .................................................... 55 
5.3 
Replacement of Subjects .................................................................................................. 56 
6. 
STUDY PROCEDURES ......................................................................................................................... 57 
6.1 
Study Schedule of Events ................................................................................................. 57 
6.2 
Screening Evaluations ....................................................................................................... 58 
6.3 
On-Study Evaluations......................................................................................................... 58 
6.4 
End of Treatment ................................................................................................................. 58 
6.5 
Follow up/Survival ............................................................................................................. 58 
7. 
CRITERIA FOR DISEASE EVALUATION .................................................................................... 59 
7.1 
Defintions ................................................................................................................................. 59 
7.2 
Response Criteria ................................................................................................................ 62 
8. 
ADVERSE EVENTS ................................................................................................................................ 64 
8.1 
Definitions ............................................................................................................................... 64 
8.1.1 
Adverse Event ............................................................................................................... 64 
8.1.2 
Serious Adverse Event .............................................................................................. 65 
8.1.3 
Non-Serious Adverse Event ................................................................................... 66 
8.2 
Period of Observation ....................................................................................................... 66 
8.3 
Documenting and Reporting of Adverse Events by Investigator ................ 67 
8.3.1 
Assessment of Causal Relationship to Study Drug ..................................... 67 
8.3.2 
Intensity of Adverse Events ................................................................................... 68 
8.3.3 
Action Taken with Study Drug ............................................................................. 68 
8.3.4 
Definition of Outcome ............................................................................................... 69 
8.4 
Immediately Reportable Events .................................................................................. 69 
8.4.1 
Serious Adverse Events ............................................................................................ 69 
8.4.2 
Other Events Requiring Immediate Reporting ............................................ 70 
8.5 
IND Safety Reports Unrelated to this Trial ............................................................. 71 
9. 
STATISTICAL METHODS ................................................................................................................... 71 
9.1 
Study Objectives ................................................................................................................... 71 
9.1.1 
Primary ............................................................................................................................. 71 
9.1.2 
Secondary ........................................................................................................................ 71 
9.2 
Sample Size Determination ............................................................................................ 71 
9.3 
Statistical Analysis Plan.................................................................................................... 72 
9.4 
Efficacy Analysis ................................................................................................................... 72 


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9.5 
Analysis of Demographic and Baseline Characteristics .................................. 73 
9.6 
Analysis of Safety Data ...................................................................................................... 73 
10. 
DATA AND SAFETY MONITORING .......................................................................................... 73 
10.1 Data Integrity and Safety Committee ........................................................................ 73 
10.2 On-Site Monitoring .............................................................................................................. 74 
10.3 Principal Investigator Responsibilities ................................................................... 74 
11. 
EMERGENCY PROCEDURES ........................................................................................................ 74 
11.1 Emergency Contact ............................................................................................................. 74 
11.2 Emergency Identification of Investigational Products .................................... 74 
11.3 Emergency Treatment ....................................................................................................... 74 
12. 
ADMINISTRATIVE CONSIDERATIONS ................................................................................... 75 
12.1 Good Clinical Practice ........................................................................................................ 75 
12.2 Institutional Review Board ............................................................................................. 75 
12.3 Delegation of Investigator Responsibilities .......................................................... 75 
12.4 Subject Information and Informed Consent .......................................................... 76 
12.5 Confidentiality ....................................................................................................................... 76 
12.6 Protocol Amendments ....................................................................................................... 76 
12.7 Case Report Forms .............................................................................................................. 76 
12.8 Record Retention ................................................................................................................. 77 
13. 
REFERENCES ........................................................................................................................................ 77 
APPENDIX ............................................................................................................................................................. 80 
PERFORMANCE STATUS CRITERIA ............................................................................................................ 80 
 
 


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ABBREVIATIONS   
AE 
adverse event 
ALT 
alanine transaminase (also SGPT) 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (also SGOT) 
AUC 
area under curve 
BID 
two times daily 
BSA 
body surface area 
BUN 
blood urea nitrogen 
Cmax 
maximum serum concentration 
Cpeak 
peak concentration 
CBC 
complete blood count 
CBR 
clinical benefit response 
CL 
clearance 
CMP 
comprehensive metabolic panel 
CNS 
central nervous system 
CR 
complete remission 
CRC 
colorectal cancer 
CRF 
case report form 
CRM 
continual reassessment method 
CT 
computed tomography 
CTC 
common toxicity criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
dL 
deciliter(s) 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor 
EU 
European Union 
FDA 
Food & Drug Administration 
FDG 
fluorodeoxyglucose 
FIP 
first-in patient or Phase 1 
FOB 
functional observational battery 
FSH 
follicle stimulating hormone 
GBM 
glioblastoma multiforme 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
gp 
glycoprotein 
HEK 
human embryonic kidney 
hERG 
human ether-à-go-go related gene 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 


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HRT 
hormone replacement therapy 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IIR 
investigator initiated research 
IBR 
Institutional Review Board 
IV 
intravenous 
IWG 
International Working Group 
kg 
kilogram(s) 
LDH 
lactic dehydrogenase 
LIC 
lead-in cohort 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
mCRC 
metastatic colorectal cancer 
MCV 
mean corpuscular volume 
MDS 
myelodysplastic syndrome 
mg 
milligram(s) 
ml 
milliliter(s) 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PET 
positron emission tomography 
PFS 
progression-free survival 
PH 
pleckstrin homology 
PI 
principal investigator 
PI3K 
phosphatidylinositol 3-kinase 
PIP2 
phosphatidylinositol (4,5)-bisphosphate 
PIP3 
phosphatidylinositol (3,4,5)-trisphosphate 
PK 
pharmacokinetics 
PO 
orally 
PR 
partial remission 
PT 
prothrombin time  
PTT 
partial thromboplastin time 
Q 
every 
QD 
once daily 
Q2W 
every two weeks 
Q3W 
every three weeks 
QW 
once weekly 
RBC 
red blood cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 


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SAE 
serious adverse event 
SC 
subcutaneous 
SD 
stable disease 
S-D 
Sprague-Dawley 
SGOT 
serum glutamic oxaloacetic transaminase (also AST) 
SGPT 
serum glutamic pyruvate transaminase (also ALT) 
t½ 
half-life 
Tmax 
time to maximum plasma concentration 
TMZ 
temozolomide 
UF 
University of Florida 
UFHCC 
University of Florida Health Cancer Center 
US  
United States 
VAMC 
Veterans Affairs Medical Center 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
A NON-RANDOMIZED PHASE IB-II PROTOCOL OF 
PACLITAXEL, CARBOPLATIN AND THE DUAL PI3K/MTOR KINASE INHIBITOR, 
PF-05212384 (GEDATOLISIB), FOR PATIENTS WITH ADVANCED OR 
METASTATIC NON-SMALL CELL CARCINOMA OF THE LUNG 
 
 
Principal Investigator: 
 
 
 
 
 
 
Signature of Investigator 
 
Dennie Jones, MD 
 
Date 
 
 
 
Printed Name of Investigator 
 
University of Florida 
 
 
 
Name of Facility 
 
Gainesville, Florida 
 
 
 
Location of Facility (City/State) 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, IRB 
procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of 
the United States Code of Federal Regulations or local 
regulations governing the conduct of clinical studies. 
 
 
 


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PROTOCOL SYNOPSIS 
 
Title: 
A 
NON-RANDOMIZED 
PHASE 
IB-II 
PROTOCOL 
OF 
PACLITAXEL, CARBOPLATIN AND THE DUAL PI3K/MTOR 
KINASE INHIBITOR, PF-05212384 (GEDATOLISIB), FOR 
PATIENTS WITH ADVANCED OR METASTATIC NON-SMALL 
CELL CARCINOMA OF THE LUNG 
Rationale: 
Background: Approximately 70% of patients with unresectable non-
small cell lung cancer (NSCLC) who receive and progress through 
frontline chemotherapy will be eligible for second line treatments. 
Any of the agents which are available for frontline therapy can be used 
in the salvage setting, though only erlotinib, docetaxel (with or 
without ramicirumab), and pemetrexed (in non-squamous cell 
carcinoma) are FDA-approved in the salvage setting based upon their 
demonstrated survival benefit in randomized phase III trials. All of 
these appear to be roughly equivalent in terms of clinical benefit, 
which is admittedly modest, with response rates <10%, clinical benefit 
rates of approximately 50%, and overall survivals of approximately 6 
months. Still, a substantial number of patients may not benefit from 
the agents in the salvage treatment setting, thus it is critical to identify 
those patients who stand to benefit the most. 
 
Hypothesis: The use of PF-05212384 in escalating dose cohorts, in 
combination with standard paclitaxel and carboplatin in subjects with 
NSCLC will be tolerated in a dose and schedule which will be 
supportive of a subsequent phase II trial, where the combinations will 
be associated with a clinical benefit (objective response, disease 
stability, and time to progression) in patients with evidence of aberrant 
PI3K or mTOR activation.  
Study 
Schema: 
Drugs / Doses / 
Length 
of 
Treatment 
 
Dose Cohort 
PF-05212384 Dose (mg, days 2, 
9, 16) 
1 
110 
2 
150 
3 
180 
 
Paclitaxel 
200 
mg/m2 
3 hour IV infusion*  
Q 21 days x 6 
cycles 
Carboplatin 
AUC = 6 
30 minute IV infusion 
immediately 
following paclitaxel 
Q 21 days x 6 
cycles 
 
Objectives: 
Primary (Phase IB) 
• To identify the maximum tolerated dose of PF-05212384 in 
combination with paclitaxel and carboplatin in subjects with 
NSCLC. 
 


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Primary (Phase II) 
• To estimate the objective rate of response of PF-05212384 in 
combination with paclitaxel and carboplatin administered to 
subjects with unresectable or metastatic NSCLC, according to 
current RECIST criteria. 
Secondary 
• To document the severity and reversibility of toxicities 
• To estimate median duration of response 
• To estimate progression-free survival for subjects on this trial with 
NSCLC treated with PF-05212384 in combination with paclitaxel 
and carboplatin 
• To estimate the overall survival 
Study Design: 
The study will consist of two phases, Ib and II. The phase Ib 
portion will study dose escalations in separate 3+3 cohorts using 
the dose levels of PF-05212384 listed in the table below. The 
phase II portion will consist of a two stage Simon design. The 
doses for paclitaxel (200 mg/m2, Q21 days) and carboplatin 
(AUC=6, Q21 days) do not adjust as part of the study design. 
 
Dose Cohort 
PF-05212384 Dose (mg, days 
2, 9, 16) 
1 
110 
2 
150 
3 
180 
 
During the first stage, cohorts of 3 participants each will be 
sequentially enrolled to each increasing dose level, beginning with 
dose level 1 (110 mg) until the first dose limiting toxicity occurs, 
or safely accrued to dose level 3. The level determined to be the 
maximal tolerable dose will have three additional subjects to 
better define tolerability prior to initiating the phase II portion.  
Once that happens, the first stage (phase Ib) will end and the trial 
will move to the second stage (phase II).  During the second stage, 
initially 10 subjects will be enrolled; in the absence of grade 3-5 
toxicity, if at least one response has been observed, then accrual 
will continue to a total of 41 subjects. 
Accrual Goal: 
A total of 41 subjects 
Inclusion 
Criteria: 
A. 
Signed IRB-approved informed consent prior to any study-
related procedures  
B. 
Age of 18 years or older 
C. 
Advanced-stage unresectable NSCLC, as confirmed by 
pathological and/or radiological analysis (subjects will be 
classified as having advanced disease if they were not eligible 


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for, or had disease progression after, surgical or locoregional 
therapies) 
D. 
Prior chemotherapy will be allowed for other invasive 
malignancies, provided therapy was completed at least five 
years before the start of protocol therapy, and participants 
have recovered from all toxicities of that prior therapy 
E. 
Participants may have received prior chemotherapy for 
NSCLC; in the phase I portion, subjects who have previously 
received paclitaxel and/or carboplatin will be allowed. In the 
phase II portion, subjects must not have received prior 
carboplatin or a taxane within the prior five years 
F. 
In the Phase II portion, subjects must have disease which 
lacks PTEN expression by immunohistochemistry, or has 
known prior activating PI3K or inactivating PTEN gene 
mutations (mutations will not be assayed for specifically) 
G. 
Eastern Cooperative Oncology Group (ECOG) performance 
status score < 2  
H. 
Life expectancy ≥ 12 week 
I. 
Participants must have measureable disease by RECIST 
criteria 
J. 
Absolute neutrophil count > 1500 mm3 (individuals with 
benign ethnic neutropenia may be enrolled if they have no 
evidence of infectious diathesis, or febrile neutropenia at the 
time of enrollment) 
K. 
Platelet count ≥ 100×109 L 
L. 
Hgb ≥ 8.5 g/dL (subjects may receive transfusions to achieve 
this, in the absence of overt bleeding) 
M. 
Total Bilirubin ≤ 2 mg/dL 
N. 
AST/ALT ≤ 3 times the upper limit of normal range 
O. 
Serum creatinine ≤1.5 times the upper limit of the normal 
range 
P. 
Women of childbearing potential (WOCBP) must be using an 
adequate method of contraception to avoid pregnancy 
throughout the study and for at least 6 months after the last 
dose of study drug to minimize the risk of pregnancy.   Prior 
to study enrollment, women of childbearing potential must be 
advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an unintentional 
pregnancy.   
 
WOCBP include any woman who has experienced menarche 
and who has not undergone successful surgical sterilization 
(hysterectomy, 
bilateral 
tubal 
ligation, 
or 
bilateral 
oophorectomy) or who is not post-menopausal. Post-
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• Amenorrhea that has lasted for ≥ 12 consecutive 
months without another cause, or 
• For women with irregular menstrual periods who are 
taking hormone replacement therapy (HRT), a 
documented serum follicle-stimulating hormone (FSH) 
level of greater than 35 mIU/mL. 
Q. 
Males with female partners of child-bearing potential must 
agree to use physician-approved contraceptive methods (e.g., 
abstinence, condoms, vasectomy) throughout the study and 
should avoid conceiving children for 6 months following the 
last dose of study drug. 
Exclusion 
Criteria: 
A. Uncontrolled cardiac disease, congestive heart 
failure, angina, arrhythmias or hypertension. 
B. Myocardial infarction or unstable angina 
within 2 months of treatment. 
C. Subjects who are carboplatin- or paclitaxel-
resistant. 
D. Known human immunodeficiency virus (HIV) 
infection or chronic active Hepatitis B (subjects 
will not be screened for this). 
E. Active clinically serious infection > CTCAE 
Grade 2. 
F. Thrombotic or embolic events such as a 
cerebrovascular accident including transient 
ischemic attacks within the past 6 months. 
G. Pulmonary 
hemorrhage/bleeding 
event 
≥ 
CTCAE Grade 2 within 4 weeks of first dose of 
study drug. 
H. Any other hemorrhage/bleeding event ≥ 
CTCAE Grade 3 within 4 weeks of first dose of 
study drug. 
I. Serious non-healing wound, ulcer, or bone 
fracture. 
J. Evidence or history of bleeding diathesis or 
coagulopathy 
K. Major surgery, open biopsy or significant 
traumatic injury within 4 weeks of first study 
drug 
L. Women or men of childbearing potential who are 
unwilling or unable to use an acceptable method to 
avoid pregnancy for the entire study period and for at 
least 6 months after the last dose of study drug 
M. Women who are pregnant or breastfeeding. 


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N. History of any other disease, metabolic dysfunction, 
physical examination finding, or clinical laboratory 
finding giving reasonable suspicion of a disease or 
condition that contraindicates the use of protocol 
therapy or that might affect the interpretation of the 
results of the study or that puts the subject at high risk 
for treatment complications, in the opinion of the 
treating physician. 
O. Prisoners 
or 
subjects 
who 
are 
involuntarily 
incarcerated. 
P. Subjects who are compulsorily detained for treatment 
of either a psychiatric or physical illness. 
Q. Subjects demonstrating an inability to comply with the 
study and/or follow-up procedures. 
Efficacy 
Assessments: 
 
For the phase Ib portion of the study, efficacy is not a primary 
objective. For the phase II portion, clinical activity, in terms or rate of 
objective response, clinical benefit, progression-free survival, 
duration of response, and overall survival will be assessed. Activity of 
this regimen, as well as toxicity, will be assessed as follows: 
 
On-Study Evaluations  
a.   Prior to initiating each treatment cycle 
b. Toxicity assessment, interim medical history and physical 
examination 
c.   Laboratory studies: 
 
CBC with leukocyte differential count 
CMP 
d.  Prior to initiating every other treatment cycle: 
CT, PET/CT or MRI scans to document tumor status. 
Statistical 
Considerations: 
Determination of Sample Size 
 
The trial will enroll up to 41 total subjects, 12 in the phase Ib portion 
and up to 29 in the phase II portion.  In the phase II portion of the 
study, so we are interested in evaluating the feasibility and safety of a 
regimen of weekly PF-05212384 (gedatolisib) in combination with 
paclitaxel and carboplatin administered to subjects with non-small cell 
lung cancer. To minimize the number of subjects exposed, the sample 
size will be determined by the anticipated response rate. A response 
rate of 20% or above to PF-05212384 in combination with paclitaxel 
and carboplatin will be of interest in subjects with previously-treated 
squamous cell lung cancer. Initially, 10 subjects will be evaluated for 
response, and if none of the 10 evaluable subjects experiences a partial 
or complete response, then the study will be terminated.  Otherwise, 
19 additional subjects will be accrued for a total of 29. The null 
hypothesis will be rejected if 4 or more responses are observed in 29 
subjects. This two stage Simon’s design yields a type I error rate of 


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0.047 and power of 0.8 when the true response rate is 0.2. A subject is 
considered eligible for toxicity evaluation if they have received at least 
one dose of PF-05212384, paclitaxel or carboplatin. A subject will be 
considered eligible for evaluation of activity if they have also received 
two cycles of therapy as planned. 
 
Statistical Analysis Plan.   
 
The maximum tolerated dose of PF-05212384, in combination with 
paclitaxel and carboplatin, will be determined by the dose escalation 
rules summarized in Sections 4.2 and 9.2.  All subjects who received 
study drug will be included in the safety analysis of this combination 
regimen. Adverse event data and corresponding toxicity grades during 
treatment and during long-term follow-up will be summarized in the 
form of tables. Incidence tables will be generated to summarize 
incidence of subjects reporting at least one episode of each specific 
adverse event, incidence of adverse events causing withdrawal and 
incidence of serious adverse events. The total number of episodes for 
each event reported (Frequency Table), the severity and attribution to 
study therapy of each episode reported (Severity Table and Attribution 
Table) will also be displayed.  Listings of adverse events by subjects 
will include the time to onset, the duration of each event, the severity 
of each event, and the relationship of the event to study therapy, 
whether it was a serious event, and whether it caused withdrawal. 
Safety data will be summarized for the overall subject group and by 
dose levels. Dose-toxicity curves will be fitted to the final data to 
estimate the toxicity rates of each dose levels.    
 
Analysis of Demographic and Baseline Characteristics 
 
The analysis of demographic characteristics (age, gender, tobacco 
abuse history and ethnicity) and baseline characteristics, including 
weight, performance status, and histologic subtype, will be primarily 
descriptive. They will be summarized in tabular format. 
 
Efficacy Analysis 
 
The primary endpoint of the phase Ib portion of this protocol is to 
determine a tolerable phase II dose of PF-05212384 in combination 
with paclitaxel and carboplatin. The primary endpoint of the phase II 
portion of this study is to determine the objective response rate of 
disease to the administration of PF-05212384 in combination with 
paclitaxel and carboplatin. A secondary endpoint of this study will be 
progression-free survival following PF-05212384 therapy.  Kaplan-
Meier mean estimates and survival curves of progression-free survival 
rates will be calculated. Secondary endpoints, including response 


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rates, clinical benefit rate (CR + PR + SD), toxicities and reversibility 
of toxicities, will be estimated along with exact 95% binomial 
confidence intervals. 
 
Safety Analysis 
 
Subjects 
will 
be 
examined 
and 
graded 
each 
cycle 
for 
subjective/objective evidence of developing toxicity according to 
NCI-CTC toxicity criteria.  Toxicities will be graded according to 
Common Toxicity Criteria (CTCAE) v4.0.  Incidence tables will be 
generated to summarize incidence of subjects reporting at least one 
episode of each specific adverse event, incidence of adverse events 
causing withdrawal, and incidence of serious adverse events. 
 
In the absence of significant treatment-related abnormalities, in 
subsequent courses subjects will not require weekly laboratory 
evaluation, but will require the documentation of return to baseline 
values prior to the initiation of subsequent courses of therapy. 
 
Missing Data 
 
Subjects lost to follow up along with other clinical variables without 
values are considered as missing data. We are not planning to do 
missing data imputation.  
Estimated 
Enrollment 
Period: 
24 months 
Estimated Study 
Duration: 
30 months 
 
 
 


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1.0 
BACKGROUND 
 
1.1 Lung Cancer Therapy 
 
The current accepted frontline therapy for unresectable NSCLC is platinum-based therapy. In 
North America, most clinicians utilize carboplatin, whereas cisplatin is offered in other parts of 
the world. The standard of care for most “fit” patients with non-mutation positive NSCLC 
(Karnofsky performance status of 70%-100%) is doublet therapy with either cisplatin or 
carboplatin, along with either paclitaxel, docetaxel, vinorelbine, or gemcitabine. Certain 
subpopulations of patients with non-squamous cell carcinomas are often offered regimens 
containing pemetrexed and/or bevacizumab. However, in multiple randomized multi-institutional 
trials, each of the doublets has a comparable response rate of approximately 20%, median 
progression-free survival of 4-5 months, median overall survival of 8-10 months, and one year 
survivals of 35-40%. Approximately 70% of patients who receive and progress through frontline 
chemotherapy will be eligible for second line treatments. Any of the agents which are available 
for frontline therapy can be used in the salvage setting, though only erlotinib, docetaxel (with or 
without ramicirumab), and pemetrexed (in non-squamous cell carcinoma) are FDA-approved in 
the salvage setting based upon their demonstrated survival benefit in randomized phase III trials. 
All of these pharmaceutical agents appear to be roughly equivalent in terms of clinical benefit, 
which is admittedly modest, with response rates <10%, clinical benefit rates of approximately 
50%, and overall survivals of approximately 6 months. However, selected epidermal growth factor 
receptor mutations are associated with much higher response rates of 50% to 70%, and prolonged 
median survivals of 17 to 38 months when treated with the EGFR tyrosine kinase inhibitor, 
erlotinib. [Jackman, et al., 2006; Rosell, et al., 2006] In a similar fashion, recent data has indicated 
superior benefit to the use of pemetrexed in nonsquamous NSCLCs. [Scagliotti et al., 2008; 
Scagliotti et al., 2009; Ciuleanu et al., 2009] There is an overwhelming need to develop regimens 
which are targeted to subgroups which may experience the most benefit from a specific agent. 
 
1.2 
PI3K/mTOR Signaling  
 
Activation of phosphatidylinositol 3-kinase (PI3K) by activating mutations in the PIK3CA gene 
(encoding the p110α catalytic subunit of PI3K) or loss of the tumor suppressor PTEN (encoding 
a lipid and protein phosphatase) is associated with growth and progression of a number of cancers 
[Itoh, 2002; Kim, 2002; Sheng, 2003]. PI3K effects on tumor growth and progression are mediated 
by two key downstream effectors, Akt and mammalian target of rapamycin (mTOR) [Jiang and 
Liu, 2009]. Treatment with wortmannin or LY294002, general PI3K chemical inhibitors, increased 
apoptosis and inhibited growth of CRC cells [Powis, 1994;Ikezoe, 2007]; however, their use is 
limited due to toxicity in vivo. Selective inhibition of downstream proteins that are directly 
involved in survival and proliferation may allow more targeted treatment with fewer toxic effects. 
The deregulation of PI3K appears to be an early event in lung carcinogenesis, as it appears in 
cytologically normal bronchial epithelia [Gustafson, 2010]. However, while PI3K activation does 
not appear to be related to cigarette smoke exposure or chronic obstructive pulmonary disease, the 
level of activity is greater in smokers than in nonsmokers; this activation does not appear to be 
related to loss of PTEN expression of PI3K gene amplification [Gustafson, 2010]. PI3K mutations 
occur in lung cancer but appear to be uncommon; one study of 1125 cases demonstrated a PI3K 
mutation in only 2% of cases (n = 23), often in the setting of another oncogene mutation, such as 


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EGFR or K-RAS [Chaft, 2011]. To date, PI3K has not been a therapeutic target in the treatment 
of lung cancer, though preclinical data indicates that PI3K may be a valid therapeutic target, even 
with a concomitant K-RAS mutation [Engelman, 2008]. 
 
The mTOR protein is a key regulator of cell 
growth by controlling mRNA translation, 
ribosome 
biogenesis, 
autophagy 
and 
metabolism [Guertin and Sabatini, 2005; 
Mayer and Grummit, 2006; Iadevaia, 2012].  
mTOR exists in two, distinct functional 
complexes: 
mTORC1 
and 
mTORC2.  
mTORC1 consists of mTOR, mLST8 and 
RAPTOR (regulatory-associated protein of 
mTOR); mTORC2 
consists 
of mTOR, 
mLST8,  RICTOR (rapamycin-insensitive 
companion 
of 
mTOR), 
Sin1 
and 
PROTOR/PRR5 (Fig. 1). When complexed 
with its cellular receptor, FKBP12 (FK506 
binding protein-12), rapamycin, a macrocyclic lactone, binds directly to mTOR to inhibit 
mTORC1.  
 
mTOR is a central modulator of proliferative signal transduction. Biomarkers indicate that the 
mTOR growth pathway is hyperactive in certain cancers suggesting mTOR as an attractive target 
for cancer therapy. Current dogma suggests that cancers, such as CRC, that are addicted to elevated 
Akt signaling are dependent upon downstream activation of mTOR signaling to drive 
tumorigenesis. Preclinical studies have shown that the mTOR pathway components mTOR, Raptor 
and Rictor are significantly over expressed in CRC tissues and cell lines.    
 
1.3 
PF-05212384 
 
PI3K-α is a central component in the PI3K/Akt/mTOR signaling pathway. Activation of this 
pathway is associated with the initiation and maintenance of numerous tumor types, poor prognosis 
and poor survival in patients with various lymphatic tumors and cancers, and resistance to targeted 
anticancer therapies and conventional cytotoxic agents. PF-05212384 (PKI-587; WYE-129587; 
chemical name 1-[4-(4-Dimethylaminopiperidine-1-carbonyl)phenyl]-3-[4-(4,6-dimorpholin-4-
yl-[1,3,5]triazin-2-yl)phenyl]urea) is a novel, pan class I dual inhibitor of PI3K and mTOR. PF-
05212384 has been shown to decrease cell survival and proliferation and increase apoptosis in 
both in vitro and in vivo models, thus acting not only as a cytostatic agent but also as an agent that 
can cause tumor regression. The antitumor efficacy of PF-05212384 has been shown when used 
as a single agent and in combination with other anticancer therapies in continuous and intermittent 
dosing regimens. PF-05212384 is expected to prove effective in the treatment of human cancers 
in the clinical setting. PF-05212384 is being developed for the treatment of advanced solid tumors 
that have are known to have high occurrence mutations/alterations in the PI3K/mTOR pathway. 
PF-05212384 can be administered IV weekly or aligned with a patient’s chemotherapy regimen 
and will be evaluated first as a monotherapy and then in combinations with other anticancer 
therapies. A single agent phase I dose of 154 mg/m2/week has been established [Shapiro, 2015]. 
Fig. 1.  Schematic diagram of PI3K/Akt/mTOR 
pathway. 


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Optimized regimens for PF-05212384 will be evaluated for safety, tolerability, and efficacy in 
patients with advanced solid tumors. PF-05212384 refers to the free base. The free base form will 
be used in the clinical studies. 
 
Laboratory Code:  
PF-05212384 
Molecular Weight:  
615.73 Daltons (Da.) 
Chemical Structure: 
 
Chemical Name:  
1-[4-(4-Dimethylaminopiperidine-1-carbonyl)phenyl]-3-[4-(4,6- 
dimorpholin-4-yl-[1,3,5]triazin-2-yl)phenyl] urea. 
Molecular Formula:  C32H41N9O4 
Physical Description:  White to beige powder 
 
The drug product is a lyophilized powder or cake in a glass vial, which 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 injection for administration as an intravenous (IV) infusion. 
This formulation contains precedented excipients, with appropriate packaging and storage 
conditions.  
 
1.3.1 Nonclinical Toxicity 
 
Adverse effects in the 3-cycle dose-ranging and/or 8-cycle repeat-dose toxicity studies in rats and 
dogs included mortality (in rats); testicular tubular degeneration (in rats and dogs); weight loss (in 
rats and dogs); ulcerations of the skin (in rats); ulcerations in oral mucosa (in dogs); and decreases 
in thymic cellularity (in dogs). In the 8-cycle toxicity studies, animals were selected before 
initiation of dosing and assigned to a 12-week recovery period after the end of the dosing phase. 
Observations made in the first 16 days of the recovery period showed reversibility of some PF-
05212384-related effects, as described below. PF-05212384 was generally tolerated after IV 
infusions up to 5 mg/kg per cycle in rats and dogs.  
 


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In the 3-cycle study in rats, 2 animals died after the first dose of 25 mg/kg. In the 8-cycle study in 
rats, no adverse effects were observed in rats given ≤5 mg/kg PF-05212384 per cycle. In the 8-
cycle rat study, testicular tubular degeneration, adverse weight loss (correlated with decreased food 
consumption), and focal ulcerations of the skin were observed in rats given 10 mg/kg per cycle; in 
addition, 1 rat given 10 mg/kg per cycle was euthanized because of a progressively worsening 
focal ulceration at the junction of the tail and body. The 16-day recovery data in rats given 10 
mg/kg per cycle showed reversibility of the PF-05212384-related weight loss and food 
consumption decreases, and focal lesions on the tail resolved in 3 of 4 rats by recovery day 16. In 
the 8-cycle toxicity study in dogs, adverse testicular tubular degeneration was observed at all 
dosages (0.5, 1.5, and 5 mg/kg per cycle). In dogs given 5 mg/kg per cycle, adverse weight loss, 
ulcerations in the oral mucosa, and decreases in thymic cellularity were observed. During the first 
16 days of the recovery period, there was evidence of reversibility of weight changes in dogs given 
5 mg/kg per cycle, and the PF-05212384-related oral ulcerations were resolved. Apart from the 
observations of adverse testicular tubular degeneration, the highest dose in the 8-cycle study that 
did not cause any severe, irreversible toxicity in dogs was 5 mg/kg per cycle. Safety updates will 
be provided on antemortem evaluations and observations and clinical and anatomic pathology 
evaluations from the recovery periods of the 8-cycle toxicity studies in rats and dogs. 
 
1.3.2 Nonclinical Safety Pharmacology 
 
Single-dose safety pharmacology studies in male rats infused with 0, 5, or 15 mg/kg indicated that 
PF-05212384 had no effects on central nervous system (CNS) function at the highest dose tested 
and had no effects on the respiratory system at the 5-mg/kg dose. Administration of 15 mg/kg PF-
05212384, the highest dosage tested and a dosage 3 times greater than the maximum tolerated dose 
(5 mg/kg) in rats after 3 doses (1 dose/4 days), was associated with adverse decreases in respiratory 
rate and/or tidal volume, resulting in decreases in mean minute volume of 174 mL/minute (-23%), 
132 mL/minute (-37%), 160 mL/minute (-25%), and 177 mL/minute (-24%) compared with 
vehicle control values at the 0.25-, 3-, 6-, and 24-hour post-dose assessments, respectively. These 
values were below the mean historical control range of 205 to 339 mL/minute. No statistically 
significant decreases in minute volume were observed at 48- or 72-hour post-dose assessments. 
Based on the magnitude and duration of the decreases in minute volume at 15 mg/kg, the decreased 
respiratory values were considered to be adverse. A cardiovascular study in male and female 
beagle dogs showed statistically significant adverse elevations in heart rate and arterial blood 
pressure at IV doses of 5 mg/kg but not at 0.5 or 1.5 mg/kg. The study found no effects at any dose 
on electrocardiogram (ECG) parameters, including corrected QT (QTc) interval prolongation or 
shortening, abnormal morphologic waveform changes, or abnormal atrial or ventricular 
arrhythmias. Additionally, results of a human ether-à-go-go related gene (hERG) assay indicated 
that PF-05212384 did not produce any inhibition of the hERG potassium ion current at 
concentrations up to 3 μM (1847.1 ng/mL). 
 
1.3.3 Nonclinical Pharmacology 
 
1.3.3.1 Brief Summary 
 
The PI3K discovery project identified PF-05212384 in enzyme assays that measured activity of 
class I PI3Ks and mTOR. PF-05212384 is an ATP-competitive, triazine-scaffold compound that 


U F -S T O -L U N G - 0 0 2 
 
2 0 1 9- 0 1- 1 0 
 
C O N FI D E N TI A L  
2 0 
Versi o n 1. 9 
is a pa n class I PI 3 K i n hi bit or wit h a 0. 4 n M I C 5 0 a gai nst PI 3 K-α.  M uta nt  f or ms  of  PI 3 K -α 
re p orte d t o ha v e ele vate d li pi d ki nase acti vit y [ Cars o n et al, 2 0 0 8] were i n hi bite d b y P F - 0 5 2 1 2 3 8 4 
at c o nce ntr ati o ns (I C 5 0 = 0. 6 t o 0. 8 n M) e q ui vale nt t o t h ose effecti ve o n wil d t y p e ( wt) PI 3 K -α. 
T he  class  I  PI 3 K  β,  δ,  a n d  γ  ( ga m ma) e nz y me  is of or ms  were  i n hi bite d  at  P F - 0 5 2 1 2 3 8 4 
c o nce ntr ati o ns 1 5- t o 2 0-f ol d hi g h er t ha n t hat of PI 3 K- α, s u g gesti n g a s mall de gree of s electi vit y. 
T he m T O R ki nase i n hi biti o n b y P F -0 5 2 1 2 3 8 4 (I C 5 0 = 1 n M) i n dicate d t hat t his c o m p o u n d was 
esse ntiall y a n e q ui p ote nt PI 3 K a n d m T O R i n hi bit or. F urt her c h aracterizati o n of P F - 0 5 2 1 2 3 8 4 
a gai nst a p a nel of 2 3 6 h u ma n pr otei n ki nases (I n vitr o ge n) c o nfir me d t h at P F -0 5 2 1 2 3 8 4 w as a 
hi g hl y selecti ve a n d p ote nt i n hi bit or of class I PI 3 Ks a n d m T O R ( R P T -7 6 6 7 1). I n t his pa nel o nl y 
Fra p 1 ( m T O R) a n d B -Raf ( wt a n d V 6 0 0 E m uta nt) were i n hi bite d b y P F -0 5 2 1 2 3 8 4 ( R P T - 7 6 6 7 1). 
S u bse q ue nt I C 5 0 v a l ues of 1 0 μ M were d eter mi ne d f or P F-0 5 2 1 2 3 8 4 v ers us b ot h B -Raf e nz y mes. 
T he I C 5 0 val u es f or P F -0 5 2 1 2 3 8 4 a gai nst all ot her ki nases i n t he I n vitr o ge n 2 3 6 pa nel were > 1 
μ M ( R P T -7 6 6 7 1). A d diti o nall y, P F -0 5 2 1 2 3 8 4 w as teste d i n h o use a gai nst t he PI K Ks A T R a n d 
S M G -1, a n d res pecti ve I C 5 0 val ues w ere > 1 0, 0 0 0 n M a n d 5 n M. P F -0 5 2 1 2 3 8 4 i n hi bite d t he li pi d 
ki nase acti vit y of class I PI 3 Ks a n d als o t he S/ T ki nase acti vit y of m T O R. Class I PI 3 Ks c o n v ert 
p h os p hati d yli n osit ol  ( 4, 5) -bis p h os p hate  ( PI P 2)  t o  p h os p hati d yli n osit ol  ( 3, 4, 5) -tris p h os p hat e 
( PI P 3) at t he i n ner cell me m bra ne [ E n gel ma n , 2 0 0 6;  S ha w & Ca ntle y, 2 0 0 6]. PI P 3 is b o u n d b y 
t he plec kstri n h o m ol o g y ( P H) d o mai ns of b ot h P D K 1 a n d A kt S/ T ki nases res ulti n g i n t heir cl ose 
pr o xi mit y at t he i n ner cell me m bra ne w h ere P D K 1 p h os p h or ylates (at T 3 0 8) a n d acti vates A kt 
[ Alessi, 1 9 9 7]. I n lie u of directl y m o nit ori n g cell ular PI P 3 le vels, P F-0 5 2 1 2 3 8 4 i n hi biti o n of PI 3 K 
was de m o nstrate d b y p ote nt (I C 5 0 < 3 0 n M) s u p pressi o n of A kt p h os p h or yl ati o n at T 3 0 8. F ull 
acti vati o n of A kt ki nase o cc urs w h e n t he m T O R c o ntai ni n g tar get of ra pa m yci n c o m ple x ( T O R C) -
2 pr otei n c o m ple x p h os p h or ylat es A kt at t he S 4 7 3 site [ Sar bass o v, 2 0 0 5]. P ote nt (I C 5 0 < 3 0 n M) 
s u p pressi o n of A kt p h os p h or ylati o n at S 4 7 3 w as als o ca use d b y P F-0 5 2 1 2 3 8 4. P F -0 5 2 1 2 3 8 4 d i d 
n ot affect t he o verall A kt c o nte nt i n M D A 3 6 1 cells, i n dicati n g p h os p h o -A kt ( p A kt) s u p pressi o n 
was a n ot a n artifact of n o ns pecific c o m p o u n d c yt ot o xicit y. B ot h of t he m T O R ki nase c o ntai ni n g 
pr otei n c o m ple x es, T O R C 1 a n d T O R C 2, were i n hi bite d b y P F - 0 5 2 1 2 3 84. A n e x a m ple of P F -
0 5 2 1 2 3 8 4 effect o n T O R C 1 is s u p pressi o n of 4 E B P 1 p h os p h or yl ati o n b y t he T O R C 1 pr otei n 
c o m ple x. Ca p -de pe n de nt pr otei n tr a nslati o n is c o ntr olle d b y 4 E B P 1 [ Gi n gras, 1 9 9 8]. T O R C 1 
p h os p h or ylati o n  of  4 E B P 1  was  i n hi bite d  at  a n  I C 5 0 c o nce ntrati o n  < 3 0  n M.  P F - 0 5 2 1 2 3 8 4 
s u p pressi o n of A kt p h os p h or ylati o n le d t o t he c o nse q ue nt i n hi biti o n of p h os p h or ylati o n of A kt 
effect or pr ot ei ns. A kt ki nase r e g ulates, b y p h os p h or ylati o n, a n u m ber of d o w nstrea m effect or 
pr otei ns t hat i n t ur n re g ulate pr otei n s y nt hesis, gl uc ose meta b olis m, pr oliferati o n, a n gi o ge nesis, 
a n d cell s ur vi val [ Alt o mare & T esta, 2 0 0 5]. E x a m ples of A kt effect ors are: E N O S, w hic h ge nerates 
nitr o us o xi de i n bl o o d vessels a n d is i n v ol ve d i n re g ul ati o n of v asc ular f u n cti o n a n d a n gi o ge nesis 
[ F ult o n, 1 9 9 9], a n d G S K-3, a n seri ne/t hre o ni ne pr otei n ki nase t hat re g ulates cell c ycle pr o gressi o n 
a n d  gl uc os e  meta b olis m  [ Cr oss,  1 9 9 5].  A kt  p h os p h or ylati o n  of  E N O S  o n  S 1 1 7 7  ca uses  its  
acti vati o n, w hereas A kt p h os p h or ylati o n of S 9/ S 2 1 of G S K -3 α/ G S K -3 β  i n hi bits  t heir f u ncti o n 
[ F ult o n, 1 9 9 9; Cr oss, 1 9 9 5]. P F -0 5 2 1 2 3 8 4 p ote ntl y s u p presse d t he p h os p h or ylati o n of b ot h of 
t hese  A kt  eff ect ors  at  I C5 0 c o nce ntrati o ns  < 3 0  n M.  A n ot her  P F -0 5 2 1 2 3 8 4  effect  t hat  was  
partic ularl y e vi de nt i n M D A 3 6 1 cells was t he i n d ucti o n of clea ve d P A R P. P A R P is a pr otei n 
i n v ol ve d i n D N A r e pair a n d pr o gra m me d cell deat h [ Maira, 2 0 0 8; Te w ari, 1 9 9 5]. P A R P clea va ge 
b y cas pase 3 f acilitates cell ular disasse m bl y a n d ser ves as a m ar ker of cells u n der g oi n g a p o pt osis 
[ Maira, 2 0 0 8; Te wari, 1 9 9 5]. I n t u m or cells, PI 3 K pat h wa y acti vati o n of A kt ki nase i n hi bits t he 
acti vati o n of vari o us cas pases (e. g., cas p ase 3) i n v ol ve d i n pr o gra m me d cell deat h (a p o pt osis). I n 
M D A 3 6 1, P F -0 5 2 1 2 3 8 4 s u p pressi o n of A kt p h os p h or ylati o n c oi n ci de d wit h detecta ble cl ea ve d 


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PARP at 30 nM PF-05212384, and increased amounts of cleaved PARP at concentrations ≥100 
nM. Cleaved PARP was detected in MDA361 breast tumor cells exposed to PF-05212384 for as 
little as 1 hour (at ≥100 nM PF-05212384) (RPT-76671), and 24-hour exposure of MDA361 to 
≥300 nM PF-05212384 caused overt cell death in >50% of cells. The potency of PF-05212384 to 
inhibit Akt phosphorylation and induce cleaved PARP in MDA361 was compared to an advanced 
(phase 2) PI3K/mTOR inhibitor (WYE-125739, BEZ235 Novartis) [Maira, 2008] and also to a 
highly selective mTOR kinase inhibitor (WYE-125132, with IC50 against mTOR=0.3 nM; IC50 
against PI3K-α = 1 μM). WYE-125132, the selective mTOR inhibitor, did not affect Akt 
phosphorylation at T308 (as expected), and all three compounds suppressed Akt phosphorylation 
at S473 (as expected). Suppression of Akt phosphorylation at T308 demonstrates compound effect 
on PI3K activity, whereas suppression of Akt phosphorylation at S473 signifies compound effect 
on the TORC2 kinase complex.  
 
1.3.3.2 Safety Pharmacology 
 
The safety pharmacology studies included in this section were conducted by Wyeth and/or its 
contractor under Good Laboratory Practice (GLP) regulations. Quality Assurance Statements and 
compliance information can be found in the reports for these studies. For studies with audited 
reports, there were no known deviations or omissions that affected the quality or integrity of the 
data. The safety pharmacology of PF-05212384 was characterized for the central nervous system 
(CNS) and respiratory system in male rats, and for the cardiovascular system in an in vitro human 
ether-à-go-go related gene (hERG) potassium ion channel assay and in vivo in male and female 
dogs. These studies are summarized below.  
 
1.3.3.3 Central Nervous System 
 
PF-05212384 was administered to male Sprague-Dawley (S-D) rats (8/group) as a single 5-minute 
IV infusion dosage of 0, 5, or 15 mg/kg, based on a dose volume of 5 mL/kg (RPT-76759). The 
control group received the vehicle consisting of 0.3% L-lactic acid, 5% D-mannitol, sterile water 
for injection, and 1 N sodium hydroxide for pH adjustment. The control dosing formulation also 
contained 5% dextrose for injection. CNS function was evaluated using a functional observational 
battery (FOB), measurement of forelimb and hind limb grip strength, and measurement of rectal 
temperature. These evaluations were conducted approximately 24 hours before dosing and at 0.25, 
3, 6, 24, 48, and 72 hours after dosing to ensure that the potential effects of PF-05212384 were 
evaluated across a range of plasma test article concentrations based on current pharmacokinetic 
data (time to peak concentration [tmax] was at the termination of infusion, with an apparent 
elimination half-life [t1/2] of 11.5 hours. Mortality, clinical condition, and body weights also were 
evaluated. Animals were euthanized after the last post-dose CNS evaluation. There were no PF-
05212384-related effects on FOB parameters, grip strength, or rectal temperature for animals given 
5 or 15 mg/kg, and there was no mortality or moribundity in this study. PF-05212384-related 
clinical signs included decreased feces (days 2 to 4) in the 15 mg/kg dosage group, and dose-
dependent body-weight loss (day 1 to the 48-hour post-dose assessment) of 4% and 13% in the 5 
and 15 mg/kg dosage groups, respectively. Body weight gain (2% to 4%) was observed in all 
dosage groups from days 3 to 4. In conclusion, PF-05212384 administered by 5-minute IV infusion 
to male rats as a single dosage of 0, 5, or 15 mg/kg did not produce any effects on CNS function. 
The NOEL for PF-05212384 on CNS function was 15 mg/kg, the highest dosage tested and a 


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dosage that is 3 times greater than the MTD (5 mg/kg) in rats after 3 doses (1 dose/4 days) of PF-
05212384.  
 
1.3.3.4 Respiratory System 
 
PF-05212384 was administered to male Sprague-Dawley rats (8/group) as a single 5-minute IV 
infusion dosage of 0, 5, or 15 mg/kg, based on a dose volume of 5 mL/kg (RPT-76760). The control 
group received the vehicle consisting of 0.3% L-lactic acid, 5% D-mannitol, sterile water for 
injection, and 1 N sodium hydroxide for pH adjustment. The control dosing formulation also 
contained 5% dextrose for injection. Using head out plethysmography, respiratory rate and tidal 
volume were recorded approximately 24 hours before dosing and at approximately 0.25, 3, 6, 24, 
48, and 72 hours after dosing. Minute volume was calculated. The timing of these respiratory 
evaluations was chosen to ensure that the potential effects of PF-05212384 were evaluated across 
a range of plasma test article concentrations based on current pharmacokinetic data (tmax was at the 
termination of infusion, with a t1/2 of 11.5 hours). Mortality, clinical condition, and body weights 
also were evaluated. Animals were euthanized after the last post-dose respiratory system 
evaluation. There were no effects on respiratory function in animals given the vehicle control or 5 
mg/kg dosage of PF-05212384, and there was no mortality or moribundity in this study. In animals 
given 15 mg/kg of PF-05212384, a dosage that is 3 times greater than the MTD (5 mg/kg) in rats 
after 3 doses (1 dose/4 days) of PF-05212384, there were statistically significant decreases in 
respiratory rate of 22%, 17%, and 25% compared with time-matched vehicle controls at the 3-, 6-
, and 24-hour post-dose assessments, respectively. The mean values for respiratory rate at 15 
mg/kg were 121, 128, and 143 breaths/minute at the 3-, 6-, and 24-hour post-dose assessments, 
respectively, and these values are below the mean historical control range (164 to 241 
breaths/minute). There were no statistically significant decreases in respiratory rate at 15 mg/kg at 
the 48- or 72-hour post-dose assessments. A decrease in tidal volume of 20% compared with 
vehicle controls was observed at the 3-hour post-dose assessment in the 15 mg/kg dosage group. 
The mean value for tidal volume at 15 mg/kg was 1.10 mL at the 3-hour post-dose assessment, 
and this value is within the mean historical control range (1.06 to 1.66 mL). PF-05212384-related 
decreases in respiratory rate and tidal volume resulted in decreases in minute volume of 23%, 37%, 
25%, and 24% compared with time-matched vehicle control values at the 0.25-, 3-, 6-, and 24-
hour post-dose assessments, respectively. Decreases in minute volume from pre-dose values were 
30%, 47%, 36%, and 29% at the 0.25-, 3-, 6-, and 24-hour post-dose assessments, respectively, 
compared with decreases in minute volume of 8%, 15%, 12%, and 5% in the vehicle-control group 
at the same time intervals. The mean values for minute volume at 15 mg/kg were 174, 132, 160, 
and 177 mL/minute at the 0.25-, 3-, 6-, and 24-hour post-dose assessments, respectively, and these 
values are below the mean historical control range (205 to 339 mL/minute). PF-05212384-related 
clinical signs included decreased feces (days 2 to 4) and hair shedding (days 3 and 4) in the 15 
mg/kg dosage group, and dose-dependent body-weight loss (day 1 to the 48-hour post-dose 
assessment) of 3% and 11% in the 5 and 15 mg/kg dosage groups, respectively. Body-weight gain 
(2% to 5%) was observed in all dosage groups from days 3 to 4. In conclusion, PF-05212384 
administered by 5-minute IV infusion to male rats as a single dosage of 0 or 5 mg/kg produced no 
effects on respiratory function. A single IV infusion dosage of 15 mg/kg, a dosage that is 3 times 
greater than the MTD (5 mg/kg) in rats after 3 doses (1 dose/4 days) of PF-05212384, produced 
decreases in respiratory rate, tidal volume, and minute volume at 0.25 to 24 hours after dose 


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administration. Based on these results, the NOEL for PF-05212384 on respiratory function was 5 
mg/kg, when given as a single 5-minute IV infusion dosage to male rats. 
 
1.3.3.5 Cardiovascular System 
 
In Vitro hERG Potassium Ion Channel Assay 
The potential effects of PF-05212384 on the rapidly activating delayed rectifier cardiac potassium 
ion current (IKr) were examined in the in vitro hERG potassium ion channel assay (RPT-76804). 
Human embryonic kidney (HEK)-293 cells that were stably transfected with hERG cDNA were 
studied at 33oC to 35oC +2oC using patch clamp electrophysiology techniques. The effect of PF-
05212384 at concentrations of 1 μM (615.7 ng/mL, based on the molecular weight of the free base 
[615.7 g/mol]) and 3 μM (1847.1 ng/mL) on the hERG channel potassium ion current was 
evaluated. Testing of higher concentrations was not possible because of limited solubility of the 
test article. PF-05212384 did not produce inhibition of the hERG potassium ion current that was 
significantly (p≤0.05) different from the inhibition observed in cells exposed to vehicle alone. PF-
05212384 did not produce any inhibition of the hERG potassium ion current at concentrations up 
to 3 μM (1847.1 ng/mL), the highest concentration that could be tested because of solubility 
limitations. Based on the results of this study, the IC50 is >3 μM (>1847.1 ng/mL). 
 
Single-Dose Intravenous, Dogs 
PF-05212384 was administered to male and female dogs (4/gender) as a single 5-minute IV 
infusion dosage of 0, 0.5, 1.5, and 5 mg/kg, at a dose volume of 10 mL/kg and according to a 
Latin-square crossover dosing paradigm (RPT-76613). Dosing was separated by a 1-week washout 
period. Body weights were obtained within 6 days before each day of dosing, for the purpose of 
calculating the dosage to be administered. One (1) female was removed from the study after the 
second dosing because of trauma to the left eye that occurred during the exercise period; the animal 
required systemic antibiotic treatment. Data collected for this animal during dosing periods 1 and 
2 (days 1 and 8, respectively) were included in the statistical analysis, but there were no data 
collected for this animal during dosing periods 3 and 4 (days 15 and 22, respectively). The vehicle 
control stock formulation consisted of 0.3% L-lactic acid, 5% D-mannitol, and sterile water for 
injection. The control article dosing formulation was prepared by diluting control stock 
formulation with 5% dextrose for injection. Parameters collected using radiotelemetry consisted 
of arterial blood pressures (systolic, diastolic, and mean), heart rate, and lead II ECG. The 
telemetry data were collected for 60-second periods every 5 minutes, for 25 hours before and 48 
hours after dosing with vehicle control or PF-05212384. Effects on heart rate and arterial blood 
pressure were evaluated at hourly intervals in all animals at all dosages from 1 to 48 hours after 
dosing. PR, QRS, and QT intervals of the ECG were measured from readable ECGs at 5-minute 
intervals from approximately 24 hours before to 48 hours after dosing using data from all animals 
at all dosages. Effects on the ECG were evaluated every 30 minutes (nominal) during the initial 2-
hour post-dose period, a 2-hour period centered 18 hours after dose administration, and at time 
points of 7, 23, and 47 hours after dose administration to ensure characterization of potential PF-
05212384 effects across a range of plasma test article concentrations based on current 
pharmacokinetic data (tmax was at the termination of infusion, with t1/2 of 16.1 hours). Pre-dose 
ECGs were chosen to correspond with clock times approximately 24 hours before the post-dose 
time point evaluated. ECG recordings were also evaluated for rhythm disorders. Observations for 
clinical signs and mortality were performed at least once daily, beginning the day before the first 


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dose administration. Administration of PF-05212384 as a single 5-minute IV infusion dosage of 
0.5 and 1.5 mg/kg to male and female dogs did not produce changes in heart rate or arterial blood 
pressure (systolic, diastolic, or mean). Administration of PF-05212384 as a single 5-minute IV 
infusion dosage of 5 mg/kg to male and female dogs resulted in a consistent, statistically significant 
average increase in mean heart rate of 24% (22 bpm) during the 12- to 33-hour post-dose period. 
In addition, a single 5-minute IV infusion dosage of 5 mg/kg of PF-05212384 produced statistically 
significant 7% (5.9 mm Hg), and 6% (6.6 mm Hg) or 5% (7.3 mm Hg), 12% (9.3 mm Hg), and 
9% (8.6 mm Hg), respectively, during the initial 12-hour post-dose period or the 31- to 37-hour 
post-dose period, compared with vehicle control. There were no effects on the ECG parameters 
(PR, QRS, QT, and corrected QT [QTc] intervals), including no evidence of QTc prolongation or 
shortening, abnormal morphologic waveform changes, or abnormal atrial or ventricular 
arrhythmias, in any of the ECGs examined in animals after receiving the vehicle control or any 
dosage of PF-05212384. PR, QRS, and QTc intervals after administration of PF-05212384 were 
comparable with those values during the pre-dose period and after administration of vehicle 
control. There was no mortality or moribundity in this study. Clinical observations included single 
incidences of post-dose emesis after administration of the 0 (vehicle control), 0.5, and 1.5 mg/kg 
dosages, and an increased frequency (4 of 7 animals) of post-dose emesis after administration of 
the high dosage of 5 mg/kg of PF-05212384. Clinical observations of post-dose emesis in the 
cardiovascular safety pharmacology study were similar to clinical observations in the IV dose-
ranging and toxicity studies in dogs. In conclusion, administration of single 5-minute IV infusion 
dosages of PF-05212384 to male and female beagle dogs produced no effects on heart rate or 
arterial blood pressure at 0.5 and 1.5 mg/kg, and produced consistent, statistically significant 
elevations in heart rate and arterial blood pressure at 5 mg/kg. Based on the magnitude and duration 
of change, the elevations in heart rate and arterial blood pressure after administration of the high 
dosage of 5 mg/kg of PF-05212384 were considered adverse. There were no effects on the ECG, 
including no evidence of QTc prolongation or shortening, abnormal morphologic waveform 
changes, or abnormal atrial or ventricular arrhythmias, at any dosage of PF-05212384 administered 
in this study. Based on these results, the NOEL in the cardiovascular safety pharmacology study 
was 1.5 mg/kg for hemodynamic effects and 5 mg/kg for ECG effects, when given as a single 5-
minute IV infusion dosage to male and female dogs. 
 
1.3.3.6 Exposure Comparisons 
 
Blood samples for the determination of PF-05212384 concentrations were not collected in the CNS 
or respiratory safety pharmacology studies in male rats, or in the cardiovascular safety 
pharmacology study in dogs. However, data from 8-cycle (cycle = 1 dose/4 days) IV toxicity 
studies in rats and dogs are available. Exposures (peak concentration [Cpeak] and AUC) after a 
single 5-minute IV infusion dosage in the 8-cycle (1 dose/4 days) repeat-dose toxicity studies were 
compared with the exposures (Cpeak and AUC) at the MED in the MDA361 xenograft mouse model 
and with the predicted exposure (AUC) at the proposed clinical IV starting dose in the first-in-
human, dose-escalation study. Exposure comparisons are described below.  
 
CNS and Respiratory Safety Pharmacology 
After a single 5-minute IV infusion dosage of 15 mg/kg in male rats, the highest dosage 
administered in the CNS safety pharmacology study, where no effects were observed, exposure 
(Cpeak = 38,211 ng/mL and AUC = 20,277 ng•h/mL) was approximately 4.7 times the Cpeak (8202 


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ng/mL) 2 and 7.1 times the AUC (2863 ng•h/mL) at the MED of 3 mg/kg in the MDA361 xenograft 
mouse model. At the highest dosage of 15 mg/kg in the NS safety pharmacology study, exposure 
(AUC) after a single 5-minute IV infusion dosage was approximately 8.6 times the predicted 
exposure at the proposed starting dose (10 mg; AUC = 2350 ng•h/mL) in the first-in-human clinical 
study. After a single 5-minute IV infusion dosage of 5 mg/kg in male rats, the dosage where no 
effects were observed in the respiratory system safety pharmacology study, exposure (Cpeak = 
12,737 ng/mL and AUC = 6759 ng•h/mL) was approximately 1.6 times the Cpeak and 2.4 times 
the AUC at the MED in the MDA361 xenograft mouse model. Exposure (AUC) after a single 5-
minute IV infusion dosage of 5 mg/kg in male rats was approximately 2.9 times the predicted 
exposure at the proposed starting dose (10 mg) in the first-in-human clinical study. 
 
Cardiovascular Safety Pharmacology 
PF-05212384 did not produce inhibition of the hERG potassium ion channel current at 
concentrations up to 3 μM (1847.1 ng/mL). It is common practice to calculate the exposure ratio 
comparing the IC50 concentration in the hERG assay to the free fraction (non-protein bound) of 
the efficacious Cpeak [Redfern, 2003] because the perfusion medium (HEPES physiological salt 
solution) used in the in vitro hERG assay is a protein-free solution; thus, no protein binding takes 
place. Since the inhibition (0.2%) at the highest concentration tested (3 μM) was similar to the 
vehicle control, the IC50 was not calculated, but was >3 μM. Therefore, the exposure ratio was 
calculated based on the highest concentration tested in the hERG assay (3 μM; 1847.1 ng/mL), 
where there was no inhibition, and the free fraction (non-protein bound) of the efficacious Cpeak. 
At the MED (3 mg/kg) in the MDA361 xenograft mouse model, the Cpeak is 8202 ng/mL. Mean 
percent protein binding in mouse plasma is 94.6%, leaving 5.4% unbound to plasma proteins (or 
free). Therefore, the highest concentration of PF-05212384 that could be tested in the hERG assay 
(3 μM; 1847.1 ng/mL), where there was no inhibition, is 4.2 times greater than the free fraction of 
the efficacious Cpeak (443 ng/mL) in the MDA361 xenograft mouse model. After a single 5-minute 
IV infusion dosage of 1.5 mg/kg in male and female dogs, the NOEL for effects on heart rate and 
arterial blood pressure in the cardiovascular safety pharmacology study, exposure (Cpeak = 5665 
ng/mL and AUC = 3472 ng•h/mL; average of male and female values for the Cpeak and AUC) was 
approximately 0.7 times the Cpeak and 1.2 times the AUC at the MED in the MDA361 xenograft 
mouse model. Exposure (AUC) after a single 5-minute IV infusion dosage of 1.5 mg/kg in male 
and female dogs was approximately 1.5 times the predicted exposure at the proposed starting dose 
(10 mg) in the first-in-human clinical study. After a single 5-minute IV infusion dosage of 5 mg/kg 
in male and female dogs, the highest dosage administered in the cardiovascular safety 
pharmacology study, where no ECG effects were observed, exposure (Cpeak = 24,492 ng/mL and 
AUC = 14,934 ng•h/mL; average of male and female values for the Cpeak and AUC) was 
approximately 3.0 times the Cpeak and 5.2 times the AUC at the MED in the MDA361 xenograft 
mouse model. Exposure (AUC) after a single 5-minute IV infusion dosage of 5 mg/kg in male and 
female dogs was approximately 6.4 times the predicted exposure at the proposed starting dose (10 
mg) in the first-in-human clinical study.  
 
1.4 
Effects in Humans 
 
The clinical studies conducted to date on PF-05212384 (gedatolisib, Pfizer) have been conducted 
in accordance with the United States Food and Drug Administration (US FDA), Good Clinical 
Practice (GCP) regulations and EU Directive on GCP. Study designs and parameters evaluated are 


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consistent with accepted principles and practices as outlined in International Conference on 
Harmonization (ICH) guidelines. The studies are summarized briefly from the most recent version 
of the Investigator Brochure (IB) of September 2015, and reflect all data obtained prior to the 
cutoff date of 30 April 2015. 
 
As of 30 April 2015, the clinical database includes information on a total of 302 patients with solid 
tumors who have received PF-05212384 in 7 clinical trials. Of the 302 patients, 129 were treated 
with PF-05212384 as a single agent in clinical trials B2151001, B1271004 and B2151006. The 
remaining 173 patients received PF-05212384 in combination with other anti-cancer agents in 
clinical trials B1271002, B2151002, B2151005, and B2151007. The clinical safety data reported 
in the following sections are based on available data as of the data cutoff date. 
 
Completed Studies: 
 
Phase 1 Study B2151001 
B2151001 is a completed Phase 1, open-label, dose-escalation first-in patient (FIP) study of single-
agent PF-05212384 in patients with advanced solid tumors. The primary objective of Part 1 of the 
study was to determine the safety, tolerability, and maximum-tolerated dose (MTD) of single-
agent PF-05212384 administered once weekly (QW) as an intravenous (IV) infusion; secondary 
objectives included assessing pharmacokinetic (PK) parameters of PF-05212384, evaluating 
pharmacodynamic (PD) markers for target inhibition, and assessing preliminary antitumor activity. 
Part 2 of the study was conducted in patients with selected tumor types that, based on nonclinical 
considerations, are thought to be sensitive to the PI3K pathway inhibition. The primary objectives 
of Part 2 of the study were to gather additional safety information at the MTD and assess 
preliminary antitumor activity; secondary objectives included assessing PK parameters of PF-
05212384 and evaluating PD markers for target inhibition. In this study, PF-05212384 was 
administered to 77 patients with advanced solid tumors. Doses administered ranged from 10 to 
319 mg. A dose level of 154 mg IV QW (n = 42) was defined as the MTD of single agent PF-
05212384.  
 
At the MTD (154 mg) of single-agent PF-05212384, the 3 most frequently experienced Adverse 
Events (AEs; all grades) at the PF-05212384 154 mg dose level were mucosal 
inflammation/stomatitis, nausea, and decreased appetite (experienced by 57.1% [24/42], 54.8% 
[23/42], and 38.1% [16/42] of patients, respectively); the majority were Grade 1 AEs (Grade 1 
inflammation/stomatitis, nausea, and decreased appetite experienced by 47.6% [20/42], 45.2% 
[19/42], and 26.2% [11/42] of patients, respectively). The most frequent (>3 patients) Grade 3 all-
causality AEs included alanine aminotransferase (ALT) increased and asthenia (4 [9.5%] patients 
and 3 [7.1%] patients, respectively); no other Grade 3 AE was reported in more than 2 patients. 
Grade 4 all-causality AEs included hyperbilirubinemia and pulmonary embolism (1 patient each). 
Five (5) patients experienced in total seven Grade 5 all-causality AEs which included disease 
progression (3 patients) and aortic disorder, colonic obstruction, gastrointestinal stromal tumor, 
and intestinal obstruction (1 patient each). At the MTD (154 mg) of single-agent PF-05212384, 
the most frequent (>20%) laboratory abnormalities (worst grade on study, all cycles) were anemia 
(81.0%), hyperglycemia (78.6%), creatinine increased (71.4%), prothrombin time prolongation 
(64.9%), lymphopenia (absolute; 62.5%), alkaline phosphatase increased (61.9%), aspartate 
aminotransferase (AST) increased (59.5%), ALT increased (47.6%), hypoalbuminemia (45.2%), 


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hypomagnesemia (42.9%), urine protein (41.2%), hyponatremia (40.5%), partial thromboplastin 
time (37.8%), hypokalemia (31.0%), prothrombin time/International Normalization Ratio 
(28.9%), hypocalcemia (28.6%), leukocytopenia (28.6%), hyperbilirubinemia (23.8%), and 
thrombocytopenia (20.0%). 
 
Phase 2 Study B1271004 
B1271004 is a completed Phase 2, open-label, 4-arm, optimal Simon 2 stage non-comparative, 
multi-center study to assess the safety, efficacy, PK, and PD of PF-04691502 (an oral PI3K/mTOR 
inhibitor) and PF-05212384 (an IV PI3K/mTOR inhibitor). This study was conducted in adult 
female patients with recurrent endometrial cancer for whom no standard therapy is available. The 
study was initially 4-arms, although on 09 October 2012, Pfizer decided to discontinue the clinical 
development of PF-04691502 and stop further enrollment of patients into study Arms A and C. 
 
Subjects were stratified by Stathmin status (high or low, which represents activated or basal PI3K, 
respectively) during screening. The primary efficacy endpoint is the clinical benefit rate (at 16 
weeks). In a lead-in cohort (LIC), single-agent PF-05212384 at the MTD identified in the FIP 
study was found to be safe and tolerable in Japanese patients (n = 6). Clinical sites in Japan also 
enrolled patients into Arms A and D. Enrollment to B1271004 was discontinued on 23 January 
2014 following a strategic decision based on the lack of sufficient efficacy. As of the data cutoff 
date 30 April 2014 (last patient study completion date), based on data entered into the clinical 
database, a total of 46 patients (6 patients in the Japan LIC and 40 patients in Phase 2) were treated 
with PF-05212384 in the study. 
 
Phase 2 Study B2151005 
B2151005 is a completed Phase 2, randomized, open-label, 2-arm, multi-center study in patients 
with metastatic colorectal cancer (mCRC), including a LIC in Japanese patients. The primary 
objective of the study is to investigate whether PF-05212384 in combination with irinotecan is 
superior to cetuximab in combination with irinotecan in prolonging progression-free survival 
(PFS) in patients with KRAS and NRAS wild type mCRC who have progressed following prior 
treatment with irinotecan, oxaliplatin, and fluoropyrimidines. The study is also designed to confirm 
the tolerability of the recommended Phase 2 dose (RP2D) of PF-05212384 in combination with 
irinotecan in Japanese patients. As of the data cutoff date 30 April 2015, based on data entered into 
the clinical database, 19 patients have been treated in B2151005. Thirteen (13) of these patients 
have been treated with PF-05212384 in combination with irinotecan (6 out of 13 were in the Japan 
LIC) and 6 patients were randomized to the non-PF-05212384 containing treatment arm in the 
Phase 2 portion of the study. 
 
 
Phase 1 Study B2151006 
B2151006 is a completed Phase 1, open-label, single-radio-labeled dose study to investigate the 
metabolism and excretion of [14C] PF-05212384 in healthy male volunteers. The aim of the study 
is to investigate the metabolism, and excretion of [14C]-PF-05212384, to characterize plasma, 
fecal, and urinary (if necessary) radioactivity and to identify any circulating or excreted 
metabolites, if possible, following a single 89 mg dose of [14C]PF-05212384. The study was 
conducted in 6 healthy men and study was completed on 11 August 2014. A single IV infusion of 
PF-05212384 at a dose of 89 mg was well tolerated in healthy subjects evaluated in this study. 


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Phase 1b/2 Study B2151007 
B2151007 is a completed Phase 1b/2, randomized, open-label, 2-arm, multi-center study in 
patients with mCRC, including a LIC in Japanese patients. The primary objective of the Phase 1b 
portion of the study is to assess safety and to determine the MTD and RP2D of PF-05212384 in 
combination with FOLFIRI in patients treated at non-Japanese clinical sites. The primary objective 
of the Phase 2 portion is to demonstrate that PF-05212384 in combination with FOLFIRI is 
superior to bevacizumab in combination with FOLFIRI in prolonging PFS in patients with mCRC 
who have progressed on a prior oxaliplatin containing regimen. The study is also designed to 
confirm the tolerability of the RP2D of PF-05212384 in combination with FOLFIRI in Japanese 
patients. As of the data cutoff date 30 April 2015, based on data entered into the clinical database, 
17 
patients 
have 
been 
treated 
with 
PF-05212384 
in 
combination 
with 
fluorouracil/leucovorin/irinotecan (FOLFIRI) in the study. 
 
Ongoing Studies: 
 
Phase 1b Study B1271002 
B1271002 is an ongoing Phase 1b, open-label, multiple center, dose-escalation study of PF-
05212384 in combination with irinotecan and PF-05212384 in combination with PD-0325901 (an 
oral MEK inhibitor) in patients with advanced solid tumors. The primary objective of the study is 
to assess the safety and tolerability and to define the MTD of PF-05212384 in combination with 
irinotecan and PF-05212384 in combination with PD-0325901. This study is being conducted in 
parallel arms of sequential patient cohorts using a classical 3+3 study design (PF-05212384 in 
combination with irinotecan) and a zone (modified 3+3) design (PF-05212384 in combination with 
PD-0325901). For PF-05212384 in combination with irinotecan, a dose level of 110 mg weekly 
of PF-05212384 in combination with 180 mg/m2 administered every 2 weeks of irinotecan was 
defined as the MTD of this combination regimen. As of 30 April 2015, based on data entered into 
the clinical database, 44 patients with advanced cancers have been treated with PF-05212384 in 
combination with irinotecan and 36 patients with solid tumors containing KRAS or BRAF 
mutations have been treated with PF-05212384 in combination with PD-0325901, an oral inhibitor 
of MEK. 
 
Phase 1 Study B2151002 
B2151002 is an ongoing Phase 1b, open-label, 3-arm, dose-escalation, multi-center study in 
patients with advanced solid tumors. The primary objective of the study is to investigate the safety, 
tolerability, PK, and PD of PF-05212384 in combination with docetaxel, cisplatin, or dacomitinib. 
Successive cohorts of patients will receive selected doses of PF-05212384 in combination with 
selected doses of chemotherapeutic agents (docetaxel and cisplatin) or dacomitinib in 3 
independent arms on an outpatient basis. As of the data cutoff date 30 April 2015, based on data 
entered into the clinical database, patients have been treated with PF-05212384 in combination 
with cisplatin (n = 16), dacomitinib (n = 28), and docetaxel (n = 19) in Study B2151002. 
 
Investigator Initiated Research Studies 
Three (3) Investigator initiated research (IIR) studies (WI179493, WI174764, and WI179849) are 
being conducted with PF-05212384. Due to the limited clinical data available regarding the IIR 


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studies as of the data cutoff date of 30 April 2015, detailed information regarding these studies 
would be provided as part of the next IB update. 
 
Notably, in an ongoing trial of gedatolisib in combination with cisplatin-based chemotherapy, the 
presumed MTD has been safely exceeded, and patients have been accrued at a dose of 215 
mg/week, though some patients have required a dose reduction to 180 mg/m2/week (personal 
communication with T. Manali, MD, Pfizer, Inc., 8/8/2016). 
 
1.4.1 Pharmacokinetics and Product Metabolism in Humans 
 
Final analysis of the pharmacokinetic data from B2151001 with single-agent PF-05212384 
suggested that following 30-minute intravenous (IV) infusion doses, plasma PF-05212384 
concentrations declined very rapidly in the first hours, followed by a slower decline with a terminal 
phase half-life (t½) of about 35 hours. Maximum plasma concentrations (end of infusion) and total 
exposure (AUC) appeared to increase proportionally with dose over the 10-mg to 319-mg dose 
range studied following both single-dose and multiple-dose administration. No drug accumulation 
was noted with once-weekly dosing. Study B2151006 titled “A Phase One, Open-Label Single-
Radiolabeled Dose Study to Investigate the Metabolism and Excretion of [14C]PF-05212384 in 
Healthy Male Volunteers” was conducted. After administration of [14C]PF-05212384 to 6 male 
human subjects, 11.53%-14.75% of administered radioactivity was excreted in the urine and 
66.43%-73.04% of administered radioactivity was recovered in the feces. The total recovery (urine 
+ feces) from each of the subjects was in the range 80.45%-85.07% of administered radioactivity. 
Peak plasma concentrations for both total radioactivity and unchanged PF-05212384 were 
observed at the end of the 30-minute infusion. Based on ratios of PF-05212384 to total 
radioactivity for maximum observed concentration (Cmax) and area under the concentration-time 
curve from time zero to infinity (AUCinf), unchanged PF-05212384 accounted for about 82% of 
the peak radioactivity and 70% of the total radioactivity in plasma. The t½ for plasma PF-
05212384 was 37 h while the apparent t½ for total radioactivity was 126 h. Metabolism of PF-
05212384 was trace with the only identified metabolite being M5 in feces representing a mean of 
0.4% of the total dose. Two additional unknown metabolites were observed in urine representing 
a mean of 0.2% and 0.3% of the total dose. A single IV infusion of PF-05212384 at a dose of 89 
mg was well tolerated in healthy subjects evaluated in this study. 
 
1.4.2 Bioavailability 
 
A bioavailability study has not been performed. PF-05212384 is not evident in plasma following 
oral administration in animals. 
 
1.4.2.1 Population Subgroups 
 
Hepatically-Impaired Patients 
The effects of hepatic impairment on multiple-dose PF-05212384 pharmacokinetics are unknown. 
 
Renally-Impaired Patients 
The effects of renal impairment on multiple-dose PF-05212384 pharmacokinetics are unknown. 
 


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1.4.3 Pharmacokinetics in Patients 
 
Patients in Phase 2/3 
It is currently unknown whether differences exist in the pharmacokinetic profile of PF-05212384 
between patients and healthy volunteers. 
 
Pharmacokinetics in Asian and Japanese Patients 
It is currently unknown whether differences exist in the pharmacokinetic profile of PF-05212384 
between Asian (including Japanese patients) and non-Asian patients. 
 
1.4.4 Drug-Drug Interactions 
 
In vitro studies in human microsomes and hepatocytes showed that there was minimal metabolism 
of PF-05212384 in all species, including human. No drug-drug interaction assessments with PF-
05212384 have been performed in humans in vivo. However, based on the 50% inhibitive 
concentration (IC50) values determined from in vitro data for the different cytochrome P450s 
(CYPs) and the observed human plasma drug concentrations from Phase 1 Study B2151001, PF-
05212384 is not likely to inhibit the metabolic clearance of concomitant drugs that are substrates 
of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Although PF-
05212384 inhibited CYP2C8 (IC50 value: 38 microM), it is unlikely that drug-drug interactions 
involving PF-05212384 and co-administered drugs that are substrates of CYP2C8 may occur, 
based on the observed Cmax levels from Phase 1 Study B2151001. Based on in vitro data, PF-
05212384 may be considered a P-glycoprotein (P-gp) substrate, but based on findings from Phase 
1 Study B2151001 it is not considered likely to affect the pharmacokinetics and disposition of 
concomitant drugs that are P-gp substrates. 
 
Other Clinical Pharmacology Data 
Pharmacokinetic/pharmacodynamic relationships between plasma levels of PF-05212384 and 
efficacy or tolerability are unknown. 
 
1.4.5 Safety  
 
Safety 
Adverse events (AEs) are coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). The severity of the treatment emergent AEs (TEAEs) are graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.0. 
 
1.4.5.1 Single Agent PF-05212384 Studies 
 
Phase 1 (First-in-Patient) Study B2151001 of Single Agent PF-05212384 in Patients with 
Advanced Solid Tumors 
 
Study Design 
B2151001 is a completed Phase 1, first-in-patient (FIP), open-label, dose-escalation study of 
single-agent PF-05212384 in patients with advanced solid tumors. The primary objective of Part 


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1 of the study was to determine the safety, tolerability, and maximum tolerated dose (MTD) of 
single-agent PF-05212384 administered once weekly (QW) as an intravenous (IV) infusion; 
secondary objectives included assessing pharmacokinetic (PK) parameters of PF-05212384, 
evaluating pharmacodynamic (PD) markers for target inhibition, and assessing preliminary 
antitumor activity. Part 2 of the study was conducted in patients with selected tumor types with 
nonclinical features suggestive of higher sensitivity to PI3K/mTOR inhibition. The primary 
objectives of Part 2 of the study were to gather additional safety information at the MTD and assess 
preliminary antitumor activity; secondary objectives included assessing PK parameters of PF-
05212384 and evaluating PD markers for target inhibition. Patients were enrolled and dosed 
according to a modified continual reassessment method (CRM) targeting a 25% Dose Limiting 
Toxicity (DLT) rate for the MTD estimation phase of the trial. Patients were enrolled in cohorts 
of 2 to 4 patients, starting with 10 mg for the first cohort. The possible doses explored were 
identified from a fine grid of doses ranging from 10 mg to 319 mg. Starting in the second cohort, 
patients were assigned to a dose that was closest to the MTD prediction based on the CRM. The 
above model was updated after completion of each cohort’s DLT period. To prevent overly 
aggressive dose-escalation, the maximum allowed dose increase from the highest dose that was 
previously studied was limited to 4 increments at a time, (ie, no more than 107% dose increase at 
a time). In this study, PF-05212384 was administered to 77 patients with advanced solid tumors. 
Doses administered ranged from 10 mg to 319 mg. A dose level of 154 mg administered QW (n = 
42) was defined as the MTD of single agent PF-05212384. 
 
Dose-Limiting Toxicities 
DLTs were only observed at or above a PF-05212384 dose of 154 mg QW (ie, at or above the 
estimated MTD). Twelve patients experienced a total of 13 DLTs (PF-05212384 154 mg: 2 of 42 
[4.8%] patients; PF-05212384 222 mg: 5 of 7 [71.4%] patients; PF-05212384 266 mg: 3 of 8 
[37.5%] patients; and PF-05212384 319 mg: 2 of 4 [50.0%] patients). The most frequently reported 
DLT was mucosal inflammation (6 of 13 DLTs); an additional patient experienced a DLT of 
stomatitis. Each of the DLTs occurred during the active treatment phase, had an onset during Cycle 
1, and was considered by the Investigator to be treatment-related. 
 
Treatment-Emergent All-Causality Adverse Events 
At the 154 mg PF-05212384 dose level. The 3 most frequently experienced AEs at this dose level 
were nausea, mucosal inflammation, and decreased appetite experienced by 54.8% [23/42], 45.2% 
[19/42], and 38.1% [16/42] of patients, respectively. Grade 1 nausea, mucosal inflammation, and 
decreased appetite were experienced by 45.2% [19/42], 38.1% [16/42], and 26.2% [11/42] of 
patients, respectively. Overall, 11.9% (5/42) of patients experienced an AE of stomatitis, of which 
9.5% were Grade 1 AEs. 
 
Discontinuations Due to Adverse Events 
Overall, 10 patients were discontinued due to AEs (PF-05212384 10 mg, 1 patient; 89 mg, 1 
patient; 154 mg, 5 patients; 222 mg, 2 patients; and 319 mg, 1 patient). Three patients were 
discontinued due to treatment-related AEs; 2 patients discontinued at the PF-05212384 222 mg 
dose level, 1 patient due to mucosal inflammation and 1 patient due to elevated alanine 
aminotransferase, and 1 patient discontinued at the PF-05212384 319 mg dose level due to mucosal 
inflammation. 
 


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Serious Adverse Events 
Of all-causality SAEs in the Phase 1 (FIP) study B2151001 at doses approximating the MTD and 
above, the most frequent all-causality SAE at the MTD (154 mg) was disease progression, reported 
in 7.1% (3/42) of patients, followed by pain, reported 4.8% (2/42) of patients. No other SAEs were 
experienced by >1 patient at the MTD. Two patients (1 patient [10020220] treated with 154 mg 
PF-05212384 and 1 patient [10020208] treated with 319 mg PF-05212384) experienced a 
treatment-related SAE of mucosal inflammation. One patient (10050110) treated with 266 mg PF-
05212384 experienced a treatment-related SAE of hyperglycemia. One patient (10010152) who 
received a starting dose of 319 mg PF-05212384 and was dose reduced to 239 mg PF-05212384 
at Cycle 4 day 22 due to toxicity, experienced treatment-related SAEs of abdominal pain, vomiting 
and diarrhea at the reduced dose. 
 
Deaths 
In the Phase 1 (FIP) study B2151001, nine patients died on treatment or within 28 days of the last 
dose of study drug, 1 patient (10030302) died post study treatment (>28 days after the last dose of 
study drug), and 1 patient (10010014) died prior to the start of treatment. The most frequently 
reported event with a fatal outcome was disease progression (7 patients). Note that patients could 
have experienced more than 1 event with a fatal outcome. None of the deaths were considered to 
be related to treatment. 
 
Phase 2 Study B1271004 of Single Agent PF-05212384 in Patients with Advanced Endometrial 
Cancer 
 
Study Design 
B1271004 is an ongoing Phase 2, randomized open label, two-stage study of single agent PF-
05212384 at a dose of 154 mg IV QW in patients with recurrent endometrial cancer. Subjects are 
stratified by Stathmin status (high or low which was thought to represent activated or basal PI3K, 
respectively) during screening. A lead-in cohort (LIC) is also included to determine if single agent 
PF-05212384 is safe and tolerable in Japanese patients. The primary efficacy endpoint of the study 
is clinical benefit rate (at 16 weeks). As of the data cutoff date of 30 April 2015, 40 patients were 
enrolled into the Phase 2 portion (all in Stage 1) of the study and 6 patients were enrolled into the 
LIC in Japan. In the LIC for Japanese patients, 2 dose levels of PF-05212384 (89 and 154 mg IV 
QW) were tested in 3 patients per dose. 
 
Dose-Limiting Toxicities 
No formal analysis of DLTs was conducted in the study. In the Japan LIC, one patient who 
received 154 mg of PF-05212384 experienced unacceptable toxicity (Grade 3 maculopapular rash) 
during Cycle 1. 
 
Treatment-Emergent All-Causality Adverse Events 
At the 154 mg PF-05212384 dose level, the most frequently experienced AEs at this dose level 
were nausea, mucosal inflammation, diarrhea, and decreased appetite experienced by 55.0% 
[22/40], 50.0% [20/40], 45.0% [18/40], and 42.5% [17/40] of patients, respectively. These 
toxicities were all Grade 1 or 2 except for 4 patients (10.0%) with fatigue, 3 patients (7.5%) each 
with diarrhea and hypertension, 2 patients each with Asthenia, urinary tract infection and dyspnea, 
and 1 patient each with stomatitis, abdominal pain, aphthous stomatitis, large intestinal 


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obstruction, 
rectal 
hemorrhage, 
mucosal 
inflammation, 
disease 
progression, 
pain, 
hypomagnesaemia, diabetes mellitus, hypercholesterolemia, hypokalemia, hyponatremia, 
bacteriuria, lung infection, pyelonephritis, respiratory tract infection, cerebrovascular accident, 
oropharyngeal pain, pulmonary embolism, arthralgia, back pain, fistula, hematuria, proteinuria, 
urinary tract obstruction, vascular access complication, anemia, gastric cancer, and cardiac failure 
experienced Grade 3 AEs. Grade 4 events were observed in 1 patient each with pulmonary 
embolism and blood creatinine increased. 
 
Discontinuations Due to Adverse Events 
As of the data cutoff date of 30 April 2015, in the Phase 2 portion of the study, 5 patients 
discontinued due to AEs which was considered by the Investigator to be related to treatment. The 
events included pulmonary embolism in 2 patients and infusion related reaction, fatigue, and rigors 
in one patient each. As of the data cutoff date of 30 April 2015, in the Japan LIC, no patients 
discontinued due to an AE; 6 patients discontinued due to disease progression. 
 
Serious Adverse Events 
The highest numbers of all-causality-SAEs were large intestinal obstruction and urinary tract 
infection (5 events each) and disease progression (3 events). 
 
Deaths 
As of the 30 April 2015 cutoff date, 2 patients died on study (on treatment or within 28 days after 
last dose); all due to disease progression. 
 
Laboratory Abnormalities 
Most of the hematology test abnormalities were Grades 1 or 2. Grade 4 hematology test 
abnormalities were reported for platelets, white blood cells and lymphopenia (1 of 40 [2.5%] 
patient each). Most of the chemistry test abnormalities were Grades 1 or 2. Grade 4 chemistry test 
abnormalities were reported for hyponatremia (1 of 40 [2.5%] patient) and hypocalcemia (2 of 40 
[5.0%] patients). 
 
PF-05212384 Single Agent Pooled Safety Data Generated in B1271004 and 
B2151001 
The pooled safety data includes data from the 42 patients treated in B2151001 and 40 patients 
treated in the phase 2 portion of B1271004 who received PF-05212384 at a dose of 154 mg IV 
weekly. The 3 most frequently experienced AEs at this dose level were nausea, mucosal 
inflammation, and decreased appetite experienced by 54.9%, 47.6%, and 40.2% of patients, 
respectively. 
 
1.4.5.2 PF-05212384 Combination Studies 
 
Phase 1b Study B1271002 of PF-05212384 in Combination with Irinotecan and PF-05212384 
in Combination with PD-0325901 in Patients with Advanced Solid Tumors 
B1271002 is an ongoing Phase 1b, open-label, double-arm, multicenter, dose-escalation, study of 
PF-05212384 in combination with irinotecan and PF-05212384 in combination with PD-0325901 
(an oral MEK inhibitor) in patients with advanced solid tumors. The primary objective of the study 
is to assess safety and tolerability and define the MTD of PF-05212384 in combination with 


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irinotecan (Arm C) and PF-05212384 in combination with PD-0325901 (Arm D). Arm C of the 
study is being conducted in parallel arms of sequential dose levels using a classical 3+3 study 
design. In Arm C, successive cohorts of patients received escalating doses of PF-05212384 
(starting dose of 95 mg QW) in combination with irinotecan (180 mg/m2 every 2 weeks [Q2W]). 
The MTD was defined as 110 mg QW of PF-05212384 and enrollment of 20 patients with 
colorectal cancer and 10 patients with pancreatic cancer in the expansion cohort was started. Arm 
D is being conducted with a zone design, which consists of a modified 3+3 design that allows 
opening more than one dose level at the same time. In Arm D, patients receive escalating doses of 
PF-05212384 (starting dose of 110 mg QW with a maximum planned dose level of PF-05212384 
of 130 mg QW) in combination with PD-0325901 (starting dose from 2 mg BID 3 weeks on/1 
week off with the possibility to increase the dose to 4 and 6 mg BID 3 weeks on/1 week off). 
 
B1271002: PF-05212384 in Combination with Irinotecan 
Dose Limiting Toxicities 
As of the data cutoff date of 30 April 2015, DLTs were experienced by 2 patients following 
administration of PF-05212384 130 mg QW + irinotecan 180 mg/m2 Q2W. The toxicities included 
Grade 4 hypokalemia, sepsis, and febrile neutropenia (1 patient), and Grade 3 fatigue (1 patient). 
Although not strictly meeting the criteria for DLT, 3 patients enrolled at the MTD (PF-05212384 
110 mg QW + irinotecan180 mg/m2 Q2W) experienced AEs that were reported by the investigator 
as DLTs on the case report form. One patient experienced Grade 2 neutropenia, one patient 
experienced Grade 1 papular rash, and 1 patient experienced Grade 1 constipation and Grade 2 
vomiting. 
 
Treatment-Emergent All-Causality Adverse Events 
For patients treated with PF-05212384 in combination with irinotecan (Arm C), the most frequent 
(>20%) treatment emergent all-causality AEs were nausea (61.4%), diarrhea (52.3%), vomiting 
(45.5%), decreased appetite (40.9%), fatigue (34.1%), abdominal pain (31.8%), asthenia (27.3%), 
alopecia (22.7%), and anemia, constipation, mucosal inflammation, pyrexia and rash (20.5% 
each). 
 
 
Discontinuations Due to Adverse Events 
As of the data cutoff date of 30 April 2015, no patients have discontinued the B1271002 study due 
to treatment-related AEs following administration of PF-05212384 in combination with irinotecan. 
 
Serious Adverse Events 
All patients who experienced SAEs were treated with PF-05212384 130 or 110 mg QW in 
combination with irinotecan 180 mg/m2 Q2W, a dose which is at or above the MTD of PF-
05212384 (110 mg) when given in combination with irinotecan 180 mg/m2 Q2W. 
 
Deaths 
As of 30 April 2015, 3 deaths were reported in study B1271002 following administration of PF-
05212384 in combination with irinotecan. The events were cerebrovascular accident, lung 
infection, asthenia, urinary tract infection and convulsion, all unrelated to study drug. 
 
 


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Laboratory Abnormalities 
Following administration of PF-05212384 in combination with irinotecan. At the time of the data 
cutoff, data were available for 44 patients. Most of the hematology test abnormalities were Grades 
1 or 2. Grade 3 hematology test abnormalities included white blood cells in 6/44 (13.6%), 
lymphopenia and anemia in 4/44 (9.1%) each, and absolute neutrophil in 3/44 (6.8%). Grade 4 
hematology test abnormalities included neutrophils (absolute) reported in 5/44 patients (11.4%) 
and lymphopenia reported in 2/44 patients (4.5%) and white blood cells decreased reported in 1/44 
(2.3%) patients each. Most of the chemistry test abnormalities were Grades 1 or 2. Grade 3 
chemistry test abnormalities included bilirubin(total) in 2/44 (4.5%) patients, hypoalbuminemia in 
2/43 (4.3%) patients, AST and ALT in 1/44 (2.3%) patient each, alkaline phosphatase in 3/44 
(6.8%) patients, hypermagnesemia in 1/44 (2.3%) patients, hypocalcemia in 2/44 (4.5%) patients, 
hypokalemia in 3/44 (6.8%) patients, hypomagnesemia in 1/44 (2.3%) patients, hyponatremia in 
2/44 (4.5%) patients, hyperglycemia in 3/44 (6.8%) patients, and hypophosphatemia in 2/44 
(4.5%) patients. Grade 4 chemistry test abnormalities included hypokalemia reported in 1/44 
(2.3%) of patients. 
 
B1271002: PF-05212384 in Combination with PD-0325901 
Discontinuations Due to Adverse Events 
As of the data cutoff date of 30 April 2015, one patient has discontinued due to AEs (mucosal 
inflammation) following administration of PF-05212384 in combination with PD-0325901. There 
were no treatment-related SAEs observed in study B1271002 when treated with PF-05212384 in 
combination with PD-0325901 as of the data cutoff date of 30 April 2015. 
 
Deaths 
As of the data cutoff date of 30 April 2015, 5 deaths had been reported following administration 
of PF-05212384 in combination with PD-0325901. The events were disease progression, non-
small cell lung cancer, cardiac tamponade, hypercalcemia abdominal pain, and pancreatic 
carcinoma, all unrelated to study drug. 
 
Laboratory Abnormalities 
Most of the hematology test abnormalities were Grades 1 or 2. Grade 3 hematology test 
abnormalities included lymphopenia and anemia in 2/36 (5.6%) patients each, and hemoglobin 
increased, platelets and neutrophils (absolute) in 1/36 (2.8%) patients each. Grade 4 hematology 
test abnormalities included white blood cells and lymphopenia reported in 1/36 (2.8%) patients 
each. Most of the chemistry test abnormalities were Grades 1 or 2. Grade 3 chemistry test 
abnormalities included hyponatremia in 4/36 (11.1%) patients, hypokalemia in 2/36 (5.6%) 
patients and AST, ALT, alkaline phosphate, hypophosphatemia, hyperglycemia and 
hypermagnesemia in 1/33 (3.0%) patient each. Grade 4 chemistry test abnormalities included 
creatinine, hyponatremia, hypocalcemia and hypoglycemia reported in 1/36 (2.8%) patient each. 
 
Phase 1b Study B2151002 of PF-05212384 in Combination with Docetaxel, Cisplatin, or 
Dacomitinib in Patients with Advanced Solid Tumors 
B2151002 is an ongoing Phase 1b, open-label, double-arm, multicenter, dose-escalation, study of 
PF-05212384 in combination with docetaxel (Arm A), cisplatin (Arm B) or dacomitinib (Arm C) 
in patients with advanced solid tumors. The primary objective of the study is to assess safety and 
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of the study are being conducted in parallel arms of sequential dose levels using a classical 3+3 
study design. The data reflects patients treated with PF-05212384 doses of 90 110 mg IV QW in 
combination with docetaxel 75 mg/m2 IV every 3 weeks (Q3W) in Arm A and doses of 90 and 
130 mg QW in combination with cisplatin 75 mg/m2 IV Q3W in Arm B. Arm C is being conducted 
with a zone design, which consists of a modified 3+3 design that allows opening more than one 
dose level at the same time. In Arm C, patients have received PF-05212384 doses of 90 and 110 
mg IV QW in combination with dacomitinib (30 and 45 mg daily (QD). 
 
Dose Limiting Toxicities 
As of the data cutoff date of 30 April 2015, DLTs were experienced by 4 patients following 
administration of PF-05212384 + dacomitinib. The DLT included the following events; Grade 3 
maculopapular rash, Grade 2 fatigue, Grade 3 mucosal inflammation, and Grade 3 pneumonitis (1 
patient each). DLT was experienced by 1 patient following administration of PF-05212384 + 
docetaxel which included Grade 3 mucosal inflammation. There were no DLTs recorded for the 
PF-05212384+ cisplatin treated patients. At the time of the cutoff date, the MTD had not been 
established for any of the PF-05212384 combinations tested in B2151002. 
 
Discontinuations Due to Adverse Events 
As of the data cutoff date of 30 April 2015, 1 patient had discontinued due to treatment-related 
AEs pneumonitis following administration of PF-05212384 in combination with dacomitinib. One 
patient had discontinued due to treatment-related AEs thrombocytopenia following administration 
of PF-05212384 in combination with docetaxel. No patients had discontinued due to treatment-
related AEs following administration of PF-05212384 in combination with cisplatin. 
 
Deaths 
As of 30 April 2015, 6 deaths were reported in study B2151002 following administration of PF-
05212384 in combination with docetaxel, cisplatin, or dacomitinib, either during treatment, or 
within 28 days of the last dose of PF-05212384 all due to disease progression. 
 
Phase 2 Study B2151005 of PF-05212384 in Combination with Irinotecan in Patients with 
Previously Treated Metastatic Colorectal Cancer 
Study B2151005 is an ongoing Phase 2 randomized study in patients with advanced colorectal 
cancer who have received 2 prior systemic therapies in the metastatic setting. The study is designed 
to determine whether PF-05212384 in combination with irinotecan has superior progression-free 
survival (PFS) compared to cetuximab in combination with irinotecan. The study includes a non-
randomized LIC conducted at Japanese sites to evaluate the safety of PF-05212384 and irinotecan 
in Japanese patients. 
 
Demographics 
As of the cutoff date of 30 April 2015, for patients assigned to receive treatment with PF-05212384 
in combination with irinotecan, a total of 19 patients were enrolled to the trial; 13 were treated 
with PF-05212384 in combination with irinotecan (6 out of 13 were in Japan LIC), while 6 patients 
were randomized to the treatment arm containing cetuximab in combination with irinotecan. 
 
 
 


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Treatment-Emergent All-Causality Adverse Events 
For patients treated with PF-05212384 in combination with irinotecan (Arm A), the most frequent 
(>20%) treatment emergent all-causality AEs were nausea and stomatitis (69.2% each), diarrhea 
(61.5%), vomiting and decreased appetite (46.2% each), fatigue and neutropenia (38.5% each), 
alopecia and rash (30.8% each), and abdominal pain, back pain, dizziness and headache (23.1% 
each). One patient experienced SAE treated with PF-05212384 110 mg QW in combination with 
irinotecan 180 mg/m2 Q2W. 
 
Deaths 
As of 30 April 2015, no deaths were reported in study B2151005 following administration of PF-
05212384 in combination with irinotecan, either during treatment, or within 28 days of the last 
dose of PF-05212384. 
 
Phase 
1b/2 
Study 
B2151007 
of 
PF-05212384 
in 
Combination 
with 
Irinotecan/fluorouracil/leucovorin (FOLFIRI) in Patients with Previously Treated Metastatic 
Colorectal Cancer 
Study B2151007 is an ongoing Phase 1b/2 randomized study in patients with advanced colorectal 
cancer who have received 1 prior systemic therapy in the metastatic setting. The study is designed 
to determine the recommended RP2D of PF-05212384 in combination with FOLFIRI and also to 
determine whether PF-05212384 in combination with FOLFIRI has superior PFS compared to 
bevacizumab in combination with FOLFIRI. 
 
Discontinuations Due to Adverse Events 
As of the data cutoff date of 30 April 2015, no patients have discontinued due to treatment related 
AEs following administration of PF-05212384 in combination with FOLFIRI. 
 
Serious Adverse Events 
As of the data cutoff date of 30 April 2015 in patients receiving PF-05212384 in combination with 
FOLFIRI in the B2151007 trial, there were no treatment-related SAEs observed. 
 
Deaths 
As of 30 April 2015, no deaths were reported in study B2151007 following administration of PF-
05212384 in combination with FOLFIRI, either during treatment, or within 28 days of the last 
dose of PF-05212384. 
 
1.4.5.3 Investigator Initiated Research (IIR) Studies 
 
Three (3) Investigator initiated research (IIR) studies (WI179493, WI174764, and WI179849) are 
being conducted with PF-05212384. Due to the limited clinical data available regarding the IIR 
studies as of the data cutoff date of 30 April 2015, detailed information regarding these studies 
will be provided as part of the next IB update and incorporated as an amendment to the protocol. 
 
Phase 1b/2 Study WI179493 of PF-05212384 in Combination with Temozolomide in Patients 
with Recurrent Glioblastoma Multiforme Showing PI3K Pathway Activation 
This is a Phase 1b/2 study of the PI3K/mTOR Inhibitor PF-05212384 combined with 
temozolomide (TMZ) in patients with recurrent glioblastoma multiforme (GBM) showing PI3K 


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pathway activation. In this study, PF-05212384 is combined with TMZ administered at the fixed 
dose of 75 mg/m2/day for 22 days of a 28-day cycle. PF-05212384 is dosed IV on a once weekly 
schedule beginning Cycle 1, Day 1. Patients who have recurrent GBM that has evidence of 
activation of the PI3K signaling pathway; specifically, either PTEN inactivation or PIK3CA or 
PIK3R1 mutations are enrolled. The study will be conducted in two sequential parts: dose 
escalation and dose expansion. Dose escalation will utilize ascending dose levels of PF-05212384 
(90 mg, 120 mg and 150 mg) and a standard 3+3 Phase 1 design. Dose expansion will enroll 
additional patients at either the 150 mg once weekly (the single-agent MTD) dose or one of the 
lower dose levels if 150 mg once weekly is not well tolerated when combined with TMZ. In each 
of the 2 parts of the study, patients will be enrolled on 1 of 2 treatment arms, depending on whether 
surgical resection of the recurrent tumor is planned. As of 30 April 2015, no patients had been 
enrolled in this study. 
 
Study WI174764: Dose finding Study of PF-05212384 with Paclitaxel and Carboplatin Dose 
Finding Part 
The primary objective of the dose finding part is to determine the MTD and the recommended 
Phase 2 dose (RP2D) of PF-05212384 in combination with paclitaxel and carboplatin in patients 
with advanced solid tumors. The trial of this protocol will replicate this data, in part, to verify 
safety and potential activity of this regimen in NSCLC. 
 
Expansion Phase 
The primary objective of the expansion phase is to define the safety and tolerability, also after 
repeated administrations, of PF-05212384 in combination with paclitaxel and carboplatin. As of 
30 April 2015, 4 patients were enrolled in this study. 
 
Serious Adverse Events and Deaths 
As of 30 April 2015, no SAEs or deaths were reported in patients treated with PF-05212384 in 
combination with paclitaxel and carboplatin in this study. 
 
Phase 2 Study WI179849 Evaluating the Efficacy of PF-05212384 for Patients with Myeloid 
Neoplasm Secondary to Chemo-Radiotherapy (T-AML/MDS) or De Novo Relapsed or 
Refractory AML 
This is a Phase 2 clinical trial evaluating the efficacy of the dual inhibition of PI3K/Akt/mTOR 
signaling pathway by PF-05212384 for patients with myeloid neoplasm secondary to chemo-
radiotherapy (t-AML/MDS) or de novo relapsed or refractory AML. This study is being conducted 
to evaluate the efficacy of PF-05212384 on the global response after a 4-month treatment 
calculated by the proportion of complete responses, complete responses with incomplete recovery 
and partial responses according to the IWG AML and MDS criteria. The treatment is administered 
in cycles of 28 days for a period of four months or until progression. As of 30 April 2015, no 
patients were enrolled in this study. 
 
 
 
 
 


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1.4.6 QTc Prolongation 
 
Phase 1 (First-in-Human) Study B2151001 of Single Agent PF-05212384 in Patients with 
Advanced Solid Tumors 
At the MTD (154 mg), PF-05212384 was associated with a normal QTcF (ie, <450 msec) in the 
majority of patients (33/42 patients [78.6%]), with Grade 1 QTcF prolongation in 8 of 42 (19.0%) 
patients and Grade 3 QTcF prolongation in 1 of 42 (2.4%) patients. At doses above the MTD (19 
patients) there was one Grade 1 QTcF prolongation (450 msec to <480 msec [PF-05212384 266 
mg]), one Grade 2 QTcF prolongation (480 msec to <500 msec [PF-05212384 222 mg]), and no 
Grade 3 toxicity. Based on the low incidence of QTcF prolongation overall and, more specifically, 
at doses above the MTD, which suggest a lack of dose effect relationship between PF-05212384 
dose and QTcF, PF-05212384 is not likely associated with QTc interval prolongation. One patient 
(10020216, a 56-year-old female at the PF-05212384 154 mg dose level) had a maximum QTcF 
interval of ≥500 msec. However, based on patient’s concomitant medical condition that included 
hypertension, probable myocardial ischemia, and electrolyte imbalance, and the likely low serum 
concentration of the study compound (due to the elapsed time between the last PF-05212384 
administration and the appearance of the event), it is considered unlikely that the reported QTcF 
prolongation was related to the study drug. 
 
Phase 2 Study B1271004 of Single Agent PF-05212384 in Patients with Advanced Endometrial 
Cancer 
Table 6.2-45 shows QTcF changes from Phase 2 Study B1271004 with single agent PF-05212384 
following administration of 154 mg QW PF-05212384. In study B1271004, at the MTD for PF-
05212384 (154 mg) the mean QTcF interval change was 24.9 + 28.19 msec. Although there was 
greater variation as observed with the greater standard deviation, the mean change in QTcF interval 
in this study was smaller than the mean change observed in Phase 1 FIP study B2151001 (28.6 ± 
15.25 msec). PF-05212384 was associated with a normal QTcF (ie, <450 msec) in 31/39 (79.5%) 
patients. Grade 1 QTcF prolongation was documented in 6/39 (15.4%) patients and Grade 2 
prolongation was observed in 2/39 (5.1%) patients. There were no patients with QTcF ≥500 msec. 
 
Phase 1b Study B1271002 with PF-05212384 in Combination with Irinotecan and PF-05212384 
in Combination with PD-0325901 in Patients with Advanced Solid Tumors 
In study B1271002, the mean QTcF interval change was 25.6 + 15.31 msec when PF-05212384 
was combined with irinotecan and was 19.5 ± 11.14 msec when PF-05212384 was combined with 
PD-0325901; these values were similar to the mean change observed in Phase 1 FIP Study 
B2151001 (28.6 + 15.25 msec). PF-05212384 in combination with irinotecan was associated with 
a normal QTcF (ie, <450 msec) in 35/44 (79.5%) patients. Grade 1 QTcF prolongation was 
documented in 7/44 (15.9%) patients and Grade 2 prolongation was observed in 1/44 (2.3%) 
patients. There was 1 patient with QTcF ≥500 msec which was not considered medically 
significant. PF-05212384 in combination with PD-0325901 was associated with a normal QTcF 
(ie, <450 msec) in 31/36 (86.1%) patients and Grade 1 QTcF prolongation in 5/36 (13.9 %) 
patients. There were no patients with > Grade 1 prolongation. 
 
 
 


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Phase 1b Study B2151002 with PF-05212384 in Combination with docetaxel, cisplatin, or 
dacomitinib in Patients with Advanced Solid Tumors 
In study B1271002, the mean QTcF interval change was 25.6 + 15.31msec when PF-05212384 
was combined with irinotecan and was 19.5 ±1 1.14 msec when PF-05212384 was combined with 
PD-0325901; these values were similar to the mean change observed in Phase 1 FIP Study 
B2151001 (28.6 + 15.25 msec). 
 
PF-05212384 in combination with cisplatin was associated with a normal QTcF (ie, <450 msec) 
in all of the patients treated to-date in the trial. PF-05212384 in combination with dacomitinib was 
associated with a normal QTcF (ie, <450 msec) in 26/27 (96.3%) patients treated to-date in the 
trial. PF-05212384 in combination with docetaxel was associated with a normal QTcF (ie, <450 
msec) in 17/19 (89.5%) patients treated to-date in the trial. Grade 1 QTcF prolongation was 
observed in 2/27 (7.4%) patients who were treated with PF-05212384+dacomitinib and in 2/19 
(10.5%) patients who were treated with PF-05212384+docetaxel. There were no patients with > 
Grade 2 prolongation. Although there were no cases of QT prolongation in the ECGs collected in 
the study, there was a patient in whom an unscheduled ECG was performed which was documented 
as demonstrating Grade 3 QT prolongation. The patient, (10091001) was a 64-year-old man with 
primary diagnosis of HNSCC who had a history of atrial fibrillation who was enrolled in Arm C 
(PF-05212384 in combination with dacomitinib). Grade 3 QTcF prolongation was identified 5 
days following last dose of PF-05212384. At the time of the event, he was also experiencing Grade 
2 hypoxia and Grade 2 mucositis and mild hypokalemia and hypomagnesemia for which he 
received K-dur and magnesium sulphate replacement therapy. The investigator considered the QT 
prolongation as unrelated to both PF-05212384 and dacomitinib. 
 
Phase 2 Study B2151005 of PF-05212384 in Combination with Irinotecan in Patients with 
Metastatic Colorectal Cancer 
In the phase 2 study B2151005, the mean QTcF interval change was 15.7 ± 8.09 msec; these values 
were lower than the mean change observed in Phase 1 FIP Study B2151001 (28.6 + 15.25 msec). 
PF-05212384 in combination with irinotecan was associated with a normal QTcF (ie, <450 msec) 
in all 11/12 (91.7%) patients treated to-date in the trial. Grade 1 QTcF prolongation was observed 
in 1/12 (8.3%) patients. There were no patients with > Grade 2 prolongation. 
 
Phase 2 Study B2151007 of PF-05212384 in Combination with FOLFIRI Chemotherapy 
In the phase 2 study, B2151007, the mean QTcF interval change was 34.5 ± 8.09 msec; these 
values were lower than the mean change observed in Phase 1 FIP Study B2151001 (28.6 + 15.25 
msec). PF-05212384 in combination with FOLFIRI was associated with a normal QTcF (ie, <450 
msec) in 14 /16 (87.5%) patients treated to-date in the trial. Grade 1 QTcF prolongation was 
observed in 2/16 (12.5%) patients. There were no patients with > Grade 2 prolongation.  
 
 
 
 
 
 
 


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1.4.7 Efficacy 
 
Preliminary efficacy data is only available in the single agent trials B2151001 and B1271004. 
 
Phase 1 (First-in-Human) Study B2151001 with Single Agent PF-05212384 in Patients with 
Advanced Solid Tumors 
The objective response rate (ORR) of single agent PF-05212384 in 77 response evaluable patients 
with advanced solid tumors was 2.6% (partial response [PR]); overall, 13% of patients were 
determined to have achieved a clinical benefit response (CBR). 
 
Phase 2 Study B1271004 with Single Agent PF-05212384 in Patients with Advanced 
Endometrial Cancer 
As of 30 April 2015, of the 38 patients treated with PF-05212384 for whom there was tumor 
assessment data at baseline and post-baseline, 1 (2.6%) patient had a CR, 5 (13.2%) patients had 
a PR and 9 (23.7%) patients had stable disease (SD) for at least 16 weeks. Overall, 39.5% of 
patients were determined to have achieved a CBR. 
 
Phase 1b Study B1271002 of PF-05212384 in Combination with Irinotecan and PF-05212384 
in Combination with PD-0325901 in Patients with Advanced Solid Tumors 
As of 30 April 2015, of the 44 patients treated with PF-05212384 in combination with irinotecan, 
no patient had a CR, 1 (2.3%) patient had a PR and 22 (50.0%) patients had SD or no response and 
objective progression was observed in 18 (41.1%) patients. ORR was not observed in 1 (2.3%) 
patients. As of 30 April 2015, of the 36 patients treated with PF-05212384 in combination with 
PD-0325901, no patient had a CR, 3 (8.3%) patients had a PR, 7 (19.4%) patients had SD or no 
response and 17 (47.2%) patients had objective progression. An objective response was observed 
in 3 (8.3%) patients. 
 
Phase 1b Study B2151002 of PF-05212384 in Combination with Docetaxel, Cisplatin, or 
Dacomitinib in Patients with Advanced Solid Tumors 
As of 30 April 2015, of the 19 patients treated with PF-05212384 in combination with docetaxel, 
no patient had a CR, 1 (5.3%) patient had a PR, 8 (42.1%) patients had SD or no response and 6 
(31.6%) patients had objective progression. An objective response was observed in 1 (5.3%) 
patient. As of 30 April 2015, of the 16 patients treated with PF-05212384 in combination with 
cisplatin, no patient had a CR, 4 (25.0%) patients had a PR, 6 (37.5%) patients had SD or no 
response and 2 (12.5%) patients had objective progression. An objective response was observed 
in 4 (25.0%) patients. As of 30 April 2015, of the 28 patients treated with PF-05212384 in 
combination with dacomitinib, 1 (3.6%) patient had a CR, 3 (10.7%) patients had a PR, 14 (50.0%) 
patients had SD or no response and 6 (21.4%) patients had objective progression. An objective 
response was observed in 4 (14.3%) patients. 
 
Phase 2 Study B2151005 of PF-05212384 in Combination with Irinotecan in Patients with 
Previously Treated Metastatic Colorectal Cancer 
As of 30 April 2015, of the 7 patients treated with PF-05212384 in combination with irinotecan, 
no patient had a CR, 1 (14.3%) patient had a PR, 3 (42.9%) patients had SD or no response and 3 
(42.9%) patients had objective progression. An objective response was observed in 1 (14.3%) 
patient. As of 30 April 2015, of the 6 patients in LIC treated with PF-05212384 in combination 


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with irinotecan, no patient had a CR and PR, 4 (66.7%) patients had SD or no response and 2 
(33.3%) patients had objective progression. An objective response was not observed in any of the 
patients. 
 
Phase 1b/2 Study B2151007 of PF-05212384 in Combination with FOLFIRI in Patients with 
Previously Treated Metastatic Colorectal Cancer 
As of 30 April 2015, of the 17 patients treated with PF-05212384 in combination with FOLFIRI, 
no patient had a CR, 1 (5.9%) patient had a PR, 5 (29.4%) patients had SD or no response and 6 
(35.3%) patients had objective progression. An objective response was observed in 1 (5.9%) 
patient. 
 
1.5 CARBOPLATIN (CBDCA) (NSC-241240) 
1.5.1 Description 
 
Carboplatin (CBDCA) is a hydrophilic platinum coordination compound and is an analog of 
cisplatin, producing intrastrand DNA cross-links. 
 
1.5.2 Toxicology 
 
Human Toxicology: Side effects of carboplatin (CBDCA) include myelosuppression, nausea, 
vomiting, abdominal pain, diarrhea and constipation. Other toxicities include allergic reaction 
(including hypersensitivity, i.e., rash, urticaria, erythema, pruritus, bronchospasm and 
hypotension), peripheral neuropathy, paresthesias, loss of hair, hearing loss, visual disturbances 
and change in taste. Serum creatinine elevations and blood urea elevations have occurred as well 
as abnormal liver function tests and decreased serum electrolyte values. Although rare, pain, 
asthenia, cardiovascular, respiratory, genitourinary and mucosal side effects have occurred in some 
patients. Cancer-associated hemolytic uremic syndrome has been reported rarely. The renal effects 
of nephrotoxic compounds may be potentiated by carboplatin. Carboplatin is contraindicated in 
patients with a history of severe allergic reactions to cisplatin or other platinum-containing 
compounds or mannitol. This drug should not be used in patients with severe bone marrow 
depression or significant bleeding. The occurrence of acute leukemia has been reported rarely in 
patients treated with anthracycline/alkylator combination chemotherapy. 
 
Pregnancy and Lactation: Carboplatin may cause fetal harm; therefore women of childbearing 
potential should be advised to avoid becoming pregnant. 
 
1.5.3 Pharmacology 
 
Kinetics: The differences in potencies of carboplatin and cisplatin are due to differences in 
aquation rates. The initial half-life is 1.1 - 2.0 hours and the post-distributional half-life is 2.6 - 5.9 
hours. Sixty-five percent of the dose is excreted in the urine within twelve hours. Carboplatin is 
not bound to plasma proteins. 
 
Formulation: Carboplatin is supplied as a sterile lyophilized powder available in single-dose vials 
containing 50 mg, 150 mg and 450 mg of carboplatin for administration by intravenous injection. 
Each vial contains equal parts by weight of carboplatin and mannitol. Immediately before use, the 


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content of each vial must be reconstituted with either Sterile Water for Injection, USP, 5% 
Dextrose in Water, or 0.9% Sodium Chloride Injection, USP, according to the following schedule: 
 
 
Vial Strength 
Diluent Volume 
50 mg 
5 ml 
150 mg 
15 ml 
450 mg 
45 ml 
 
These dilutions all produce a carboplatin concentration of 10 mg/mL. Carboplatin can be further 
diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water or 0.9% Sodium 
Chloride Injection, USP (NS). 
 
Storage and Stability: Unopened vials of carboplatin for injection are stable for the life indicated 
on the package when stored at controlled room temperature 15° - 30°C, and protected from light. 
When reconstituted as directed, the solution of carboplatin exhibits no decomposition for 8 hours 
at room temperature (25°C). Like cisplatin, this drug should not be given through aluminum 
needles. 
 
CAUTION: The single-use lyophilized dosage form contains no antibacterial preservatives. 
Therefore, it is advised that the reconstituted product be discarded eight hours after dilution.  
 
Administration: Intravenous. 
Supplier: Carboplatin is commercially available for purchase by the third party. 
Please refer to the Physician Desk Reference and package insert for complete Information. 
 
1.6 
PACLITAXEL, Taxol® (NSC-673089) 
1.6.1 Description 
 
Chemistry: Paclitaxel is a diterpene plant product found in the needles and bark of the western 
yew, Taxus brevifolia. The marketed formulation is prepared in a semi-synthetic process. 
Molecular Weight: 853.9 
Empirical Formula: C47H51NO14 
Description: Clear viscous fluid 
 
1.6.2 Toxicology 
 
Human Toxicity: 
Dose-limiting toxicity is myelosuppression with reversible granulocytopenia, anemia, and 
thrombocytopenia. Allergic reactions occur in up to 8% of patients receiving paclitaxel as an 
intravenous infusion over 6 to 24 hours. These can be acute anaphylactoid reactions to include 
flushing, hypotension, and bronchospasm; dermatitis and pruritus are also observed. Hypertension 
has also been seen, and may be related to concomitant medication with dexamethasone. 
Premedication with diphenhydramine, cimetidine, and dexamethasone appears to diminish the 
incidence of these reactions. Neurotoxicity can include distal painful paresthesias. Rarely, this 
toxicity has required discontinuation of drug due to pain, impairment of fine motor skills, or 


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difficulty ambulating. Experience to date suggests that this neuropathy is reversible. Rarely, 
associated forms of neurotoxicity have included taste perversion, seizures, and mood changes. 
Some patients have reported vision abnormalities such as blurred vision, "flashing lights" and 
scintillating scotomata. Ischemic or infarcted colon, sometimes with involvement of other parts of 
the gastrointestinal tract, has also been seen. Patients reporting abdominal discomfort should be 
monitored closely. These events generally occurred while the patients were severely neutropenic. 
They may be most consistent with neutropenic enterocolitis (typhlitis). Although increased SGOT, 
SGPT, bilirubin and alkaline phosphatase, as well as hepatic failure and hepatic necrosis have been 
seen, one patient receiving this drug has also experienced hepatic encephalopathy, and two 
incidences of pancreatitis have been noted. Neuroencephalopathy has also been reported. 
Pulmonary toxicities that have occurred are pneumonitis and radiation pneumonitis (following 
concomitant paclitaxel and radiation). Other non-hematologic reactions include: diarrhea, 
alopecia, myalgias and arthralgias, nausea or vomiting, mucositis (stomatitis and pharyngitis), 
lightheadedness, myopathy and fatigue. Less commonly, cardiotoxicity has been associated with 
paclitaxel administration, to include arrhythmias (sinus bradycardia, ventricular tachycardia, atrial 
arrhythmia, and heart block), and myocardial infarction. Skin reactions including erythema, 
induration, tenderness, ulceration, radiation recall, rash and nail changes have occurred including 
discoloration of fingernails and separation from nail bed. 
 
Pregnancy and Lactation: Paclitaxel may cause fetal harm when administered to a pregnant 
woman. Paclitaxel has been shown to be embryo- and fetotoxic in rats and rabbits and to decrease 
fertility in rats. In these studies, paclitaxel was shown to result in abortions, decreased corpora 
lutea, a decrease in implantations and live fetuses, and increased resorption and embryo-fetal 
deaths. No information is available on the excretion of this drug in human milk. Because many 
drugs are excreted in human milk and because of the potential for serious adverse reactions in 
nursing infants, it is recommended that nursing be discontinued. 
 
1.6.3 Pharmacology 
 
Formulation: Sterile solution containing 6 mg/ml in a 5 ml vial (30 mg per vial) in 
polyoxyethylated castor oil (Cremaphor EL) 50% and dehydrated alcohol, USP, 50%. There are 
also vial sizes of 100 mg and 300 mg. 
 
Solution Preparation: Paclitaxel is reconstituted by diluting the total dose in 0.9% Sodium Chloride 
Injection, USP, or 5% Dextrose Injection, USP (D5W) to maintain a paclitaxel concentration 
between 0.3 and 1.2 mg/ml. Paclitaxel must be prepared in glass or polyolefin containers due to 
leaching of diethylhexlphthalate (DEHP) plasticizer from polyvinyl chloride (PVC) bags and 
intravenous tubing by the Cremaphor vehicle in which paclitaxel is solubilized. Each bag/bottle 
should be prepared immediately before administration. 
 
NOTE: Formation of a small number of fibers in solution (within acceptable limits established by 
the USP Particulate Matter Test for LVPs) has been observed after preparation of paclitaxel. 
Therefore, in-line filtration is necessary for administration of paclitaxel solutions. In-line filtrations 
should be accomplished by incorporating a hydrophilic, microporous filter of pore size not greater 
than 0.22 microns (e.g.: IVEX-II or IVEX-HP or equivalent) into the IV fluid pathway distal to 


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the infusion pump. Although particulate formation does not indicate loss of drug potency, solutions 
exhibiting excessive particulate matter formation should not be used. 
 
Administration of Paclitaxel: Paclitaxel, at the appropriate dose, will be given as an intravenous 
infusion as specified in the protocol, diluted in 0.9% Sodium Chloride Injection, USP, or 5% 
Dextrose Injection. Paclitaxel will be administered via an infusion control device (pump) using 
non-PVC tubing and connectors, such as the IV administration sets (polyethylene or polyolefin) 
which are used to infuse parenteral nitroglycerin. Nothing else is to be infused through the line 
where paclitaxel is being administered. 
 
Storage and stability: The intact vials of paclitaxel should be stored between 2-25°C. Based on 
stability data for Taxol® made from either natural or semisynthetic paclitaxel, stored for up to 12 
months at 40°C, potency losses were within the range of 2.0 to 2.4 percent per year. Samples stored 
for up to 3 months at 60°C lost potency at rates corresponding to 20 to 40% per year. Accordingly, 
vials left out in a warm place for a few days should still be satisfactory for use. All solutions of 
paclitaxel exhibit a slight haziness directly proportional to the concentration of drug and the time 
elapsed after preparation, although when prepared as described above, solutions of paclitaxel (0.3-
1.2 mg/ml) are physically and chemically stable for 27 hours. Vials will be labeled with a firm 
expiration date. 
 
Supplier: Paclitaxel is commercially available for purchase by the third party. 
Please refer to the Physician Desk Reference and package insert for complete information. 
 
2. STUDY POPULATION 
 
2.1 
Inclusion Criteria  
 
Subjects must meet all of the following criteria to be eligible for study participation: 
A. Signed IRB-approved informed consent prior to any study-related procedures  
B. Age of 18 years or older 
C. Advanced-stage unresectable NSCLC, as confirmed by pathological and/or radiological 
analysis (subjects will be classified as having advanced disease if they were not eligible 
for, or had disease progression after, surgical or locoregional therapies) 
D. Prior chemotherapy will be allowed for other invasive malignancies, provided therapy was 
completed at least five years before the start of protocol therapy, and participants have 
recovered from all toxicities of that prior therapy 
E. Participants may have received prior chemotherapy for NSCLC; in the Phase I portion, 
subjects who have previously received paclitaxel and/or carboplatin will be allowed. In the 
phase II portion, subject must not have received prior carboplatin or a taxane within the 
prior five years. 
F. In the Phase II portion, subjects must have disease which lacks PTEN expression by 
immunohistochemistry, or has known prior activating PI3K or inactivating PTEN gene 
mutations (mutations will not be assayed for specifically) 
G. Eastern Cooperative Oncology Group (ECOG) performance status score < 2  
H. Life expectancy ≥ 12 week 
I. Participants must have measureable disease by RECIST criteria 


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J. Absolute neutrophil count > 1500 mm3 (individuals with benign ethnic neutropenia may 
be enrolled if they have no evidence of infectious diathesis, or febrile neutropenia at the 
time of enrollment) 
K. Platelet count ≥ 100×109 L 
L. Hgb ≥ 8.5 g/dL (subjects may receive transfusions to achieve this, in the absence of overt 
bleeding) 
M. Total Bilirubin ≤ 2 mg/dL 
N. AST/ALT ≤ 3 times the upper limit of normal range 
O. Serum creatinine ≤1.5 times the upper limit of the normal range 
P. Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for at least 6 months after the 
last dose of study drug to minimize the risk of pregnancy.   Prior to study enrollment, 
women of childbearing potential must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy.   
 
WOCBP include any woman who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or who is not post-menopausal. Post-menopause is defined as: 
• Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or 
• For women with irregular menstrual periods who are taking hormone replacement 
therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of 
greater than 35 mIU/mL. 
Q. 
Males with female partners of child-bearing potential must agree to use physician-
approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the 
study and should avoid conceiving children for 6 months following the last dose of study 
drug. 
 
2.2 
Exclusion Criteria 
 
Subjects with any of the following will not be eligible for study participation: 
A. Uncontrolled cardiac disease, congestive heart failure, angina, arrhythmias or 
hypertension. 
B. Myocardial infarction or unstable angina within 2 months of treatment. 
C. Subjects who are carboplatin- or paclitaxel-resistant. 
D. Known human immunodeficiency virus (HIV) infection or chronic active Hepatitis 
B (subjects will not be screened for this). 
E. Active clinically serious infection > CTCAE Grade 2. 
F. Thrombotic or embolic events such as a cerebrovascular accident including 
transient ischemic attacks within the past 6 months. 
G. Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first 
dose of study drug. 
H. Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first 
dose of study drug. 
I. Serious non-healing wound, ulcer, or bone fracture. 
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K. Major surgery, open biopsy or significant traumatic injury within 4 weeks of first 
study drug 
L. Women or men of childbearing potential who are unwilling or unable to use an acceptable 
method to avoid pregnancy for the entire study period and for at least 6 months after the 
last dose of study drug 
M. Women who are pregnant or breastfeeding. 
N. History of any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of protocol therapy or that might affect the interpretation of the 
results of the study or that puts the subject at high risk for treatment complications, in the 
opinion of the treating physician. 
O. Prisoners or subjects who are involuntarily incarcerated. 
P. Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
illness. 
Q. Subjects demonstrating an inability to comply with the study and/or follow-up procedures. 
 
2.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
3. REGISTRATION PROCEDURES 
 
All subjects must be registered with the UF Health Cancer Center prior to participation in this trial. 
The participating site must fax or email the completed study specific eligibility checklist and 
registration forms, supporting documents and signed informed consent to the Coordinating Center. 
Unsigned or incomplete forms will be returned to the site. Once documents are received, the 
designated Research Coordinator will review them to confirm eligibility and to complete the 
registration process. If eligibility cannot be confirmed, the research coordinator will query the site 
for clarification or additional documents as needed. Subjects failing to meet all study eligibility 
requirements will not be registered and will be unable to participate in the trial. 
 
4. STUDY TREATMENT 
 
All subjects entering the screening phase will receive a unique subject number. This number will 
be used to identify the subject throughout the study. Subjects withdrawn from the study will retain 
their subject number. 
  
4.1 
Treatment Schedule/Administration 
 
This study is an open-label, non-randomized, sequentially-enrolling phase Ib-II trial in subjects 
with NSCLC who would be eligible for paclitaxel and carboplatin. 
 
 
 
 


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4.2 
Overall Treatment Plan 
 
This is a non-randomized, Phase Ib-II trial to assess clinical safety and potential benefit of PF-
05212384 when administered to subjects with NSCLC who are receiving a baseline regimen of 
paclitaxel and carboplatin. All treatment will be administered on an outpatient basis. Before the 1st 
dose of treatment, subjects will undergo clinical, pathological and radiographic tumor assessment. 
PF-05212384 will be administered IV on days 2, 9, 16 of the 21-day treatment cycle.  
 
The phase Ib portion will study dose escalations in separate cohorts using the dose levels of 
PF-05212384 listed in the table below. The phase II portion will consist of a two stage Simon 
design. The doses for paclitaxel (200 mg/m2, Q21 days) and carboplatin (AUC=6, Q21 days) 
do not adjust as part of the study design. 
 
Dose Cohort 
PF-05212384 Dose (mg, days 
2, 9, 16) 
1 
110 
2 
150 
3 
180 
 
During the first stage, cohorts of 3 participants each will be sequentially enrolled to each 
increasing dose level, beginning with dose level 1 (110 mg) until the first dose limiting 
toxicity occurs, or safely accrued to dose level 3. The level determined to be the maximal 
tolerable dose will have three additional subjects to better define tolerability prior to 
initiating the phase II portion.  Once that happens, the first stage (phase Ib) will end and the 
trial will move to the second stage (phase II).  During the second stage, initially 10 subjects 
will be enrolled; in the absence of grade 3-5 toxicity, if at least one response has been 
observed, then accrual will continue to 29 subjects. The MTD of PF-05212384 in combination 
with a platinum-based regimen appears to exceed 215 mg, and at this time there will be no attempt 
to exceed that dose level. 
 
Dose reduction or interruption of PF-05212384 for toxicity may take place at any time during the 
study.  Toxicity grading is based on NCI-CTCAE, v 4.0.3.  Dose level reductions are to the 
immediately preceding dose cohort.  If subjects do not tolerate the second dose reduction, PF-
05212384 is to be discontinued.  
 
Eligible subjects will include those with radiographically-staged locally advanced or metastatic 
NSCLC. For the phase I portion, subjects may have previously received paclitaxel and/or 
carboplatin. For the phase II portion, subjects must not have received prior carboplatin or a taxane 
within the prior five years to study enrollment.  Subjects who receive radiation therapy to any 
indicator lesion must have demonstrated progressive growth of the lesion to be assessable; be 
willing to use contraception and if females or child-bearing capacity, are neither pregnant nor 
lactating; are greater than 18 years old and have an anticipated life expectancy of at least 12 weeks; 
have normal end-organ function and limited comorbidities, and are able to provide written 
informed consent. 
 


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The initial dose of paclitaxel is 200 mg/m2. The initial dose of carboplatin is AUC=6 by modified 
Calvert formula (see below). Carboplatin is given after paclitaxel infusion is completed. Both 
drugs with be given sequentially on Day 1 of the 21-day treatment cycle (+ 3 days, to allow for 
weekends, holidays, unforeseen events not related to toxicity). Serum creatinine must be repeated 
and creatinine clearance calculated within 3 days prior to each carboplatin dose. In subjects whose 
serum creatinine is < 0.8 mg/dl, 0.8 mg/dl must be substituted in the Cockroft-Gault formula to 
calculate the estimated creatinine clearance for carboplatin dosing.  
 
Paclitaxel 
200 mg/m2 
3 hour IV infusion  
Day 1 of each 21 day 
cycle x 6 cycles 
Carboplatin 
AUC = 6 
30 minute IV infusion 
immediately following 
paclitaxel 
Day 1 of each 21 day 
cycle x 6 cycles 
PF-
05212384 
110 mg 
150mg 
180mg 
30 minute IV infusion 
Days 2, 9, 16 of each 21 
day cycle x 6 cycles 
 
 
Guidelines for Carboplatin Administration 
The carboplatin dose (mg) = AUC x (CrCl + 25) where AUC = 6 depending on the dose level. The 
creatinine clearance will be calculated using a serum creatinine obtained within 3 days prior to 
each dose. Carboplatin dose will be based on GFR* (glomerular filtration rate) based on the 
measurement of creatinine clearance where GFR is calculated using the Cockroft-Gault Formula: 
CrCI = [(140 - age) x actual body weight (kg)**] / [72 x serum creatinine***] 
Multiply this number by 0.85 if the subject is female. 
 
* GFR = calculated creatinine clearance determined using the Cockroft-Gault Formula based on 
age, weight (actual body weight) and serum creatinine. 
** Use current (actual) weight. This should be actual weight but not exceed 140% of IBW. 
*** In subjects whose serum creatinine is < 0.8 mg/dl, 0.8 mg/dl must be substituted in the 
Cockroft-Gault formula to calculate the estimated creatinine clearance for carboplatin dosing. 
 
Please note that: GFR should not exceed 125 m/min. Hence, the maximum total carboplatin dose 
should NOT exceed 900 mg. 
 
All subjects should be pre-medicated with: 
Agent   
 
Dose  
Route   
Duration 
Dexamethasone  
20 mg  
PO/IV   
12 and 6 hours prior to paclitaxel* 
Diphenhydramine  
50 mg   
IV  
 
30 minutes prior to paclitaxel 
plus one of the following: 
Ranitidine  
 
50 mg   
IV 
 
30 minutes prior to paclitaxel 
Cimetidine 
 
300 mg  
IV 
 
30 minutes prior to paclitaxel 
or 
Famotidine  
 
20 mg   
PO/IV   
30 minutes prior to paclitaxel 
 
* Alternatively, a single intravenous dose of 20 mg may be given 30 minutes 


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prior to paclitaxel injection. 
 
CAUTION: Allergic reactions may occur during or following chemotherapy administration. As a 
routine precaution, subjects enrolled in this study will be observed closely for any potential adverse 
events by the medical staff from the start of the chemotherapy infusion to one hour after the end 
of the infusion in an area with resuscitation equipment and other agents (epinephrine, prednisone 
equivalents, etc.) available. Vital signs (blood pressure, heart rate, respiratory rate and 
temperature) should be checked prior to the administration, midway through the infusion, at the 
completion of the infusion and 1 hour post the infusion. Should an allergic or infusion reaction to 
chemotherapy occur, the subject must be treated according to the best available medical practice. 
The subject’s blood pressure and heart rate should be monitored during the chemotherapy infusion. 
(Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is 
recommended.) Epinephrine and diphenhydramine for injection should be readily available during 
the infusion, for emergency treatment of hypersensitivity reactions. 
 
4.3 
Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD) 
 
During the first stage, cohorts of 3 participants each will be sequentially enrolled to each increasing 
dose level, beginning with dose level 2 (150 mg) until the first dose limiting toxicity occurs.  Once 
that happens, the first stage will end and the trial will move to the second stage.  During the second 
stage, subjects will be enrolled in cohorts of one using the Bayesian CRM design with a targeted 
dose limiting toxicity rate of 25%.  The design assumes an empiric model and a total sample size 
from both stages of 41 subjects. 
 
Definition of MTD: 
The maximum tolerated dose of PF-05212384, in combination with paclitaxel and carboplatin, 
will be determined by the dose escalation rules summarized in Section 4.2 and 9.2.   
 
Definition of DLT: 
DLT will have occurred when the subject has one or more Grade 4 hematologic or nonhematologic 
toxicities. Exceptions will be made for alopecia and non-febrile neutropenia, which are nearly 
universal with the use of any taxanes. Grade 3 or greater neuropathy will also be considered as a 
dose limiting toxicity. By convention, a DLT must occur in the first cycle of the combination and 
must be at least possibly attributed to the treatment regimen. Toxicities occurring in later cycles 
will not be considered as a DLT, though they may represent cumulative toxicities of the regimen 
and thus may limit the number of cycles which may be delivered; example of this are neuropathy 
related to cisplatin, oxaliplatin, or taxanes administration, or cardiomyopathy due to anthracycline 
or anthracenedione administration. Toxicities will be graded according to the NCI CTCAE Version 
4.0.3.  
 
4.4 
Chemotherapy Guidelines 
 
Subjects are to receive PF-05212384 at an initial dose of 110 mg on days 2, 9, and 16 of every 21-
day cycle, with paclitaxel and carboplatin as above, with adequate pre-medications and anti-
emetics, though the specific agents will be at the discretion of the treating oncologist, within 


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accepted FDA, American Society of Clinical Oncology, and National Comprehensive Cancer 
Network guidelines. 
 
In the absence of obvious rapid disease progression, subjects will receive two cycles of protocol 
therapy (six weeks) before an objective response determination is made by computed tomography 
or magnetic resonance imaging. Subjects will be reassessed radiographically every other cycle. 
Subjects will continue to receive protocol therapy until disease progression unless a complete 
remission is obtained, in which case subjects will receive at least two additional cycles of protocol 
therapy, and then may hold further active therapy at the discretion of the treating physician. 
Subjects will receive a maximum of six cycles of protocol therapy; after completion of six cycles, 
subjects may receive maintenance therapy with erlotinib, pemetrexed, or bevacizumab, as 
indicated. 
 
In the absence of a decline in performance status or comorbid disease, subjects will continue until 
documentation of disease progression, or intolerable toxicity, or six cycles, whichever occurs first. 
Subjects who experience a disease progression through protocol therapy will be offered alternative 
chemotherapy or palliative care, after discussion with his or her treating physician.  
 
Subjects who experience a CR should receive two additional cycles of protocol therapy following 
the documentation of a CR, however, no subject will receive more than six cycles of protocol 
therapy. Subjects who experience a CR due to local consolidative therapy should likewise receive 
two additional cycles of chemotherapy as described in the protocol. 
 
4.5 
Concomitant Therapy 
 
Relevant medical history should be obtained at screening and include prior medications and 
treatment history.  All medications taken within 1 week prior to screening, regardless of indication, 
should be recorded. An exception will be for any monoclonal antibodies which are received within 
the 6 weeks prior to the initiation of therapy. 
 
Any therapy or medication (except study drugs), administered from screening until 28 days after 
the last dose of either study drug, is considered a concomitant therapy or medication. However, if 
another course of anti-cancer therapy is initiated prior to the 28-day follow-up period visit; a record 
of concomitant medications will no longer be performed. If the use of any concomitant treatments 
(medications or procedures) becomes necessary, the treatment must be recorded, including the 
name of the drug or treatment, dose, route, date, indication for use, expected duration, and 
frequency of treatment. Assessment and documentation of concomitant medications will be done 
at each visit. 
 
4.5.1 Allowed Concomitant Therapy 
 
Subjects are to continue their medications for chronic non-malignant diseases that they were 
receiving prior to study enrollment. Antibiotics are not an exception to enrollment, but must have 
been completed for at least 7 days prior to initiating study therapy. There may still be potential ill-
defined interactions between PF-05212384 and CYP3A4 inhibitors and CYP3A4 promoters.  


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Although caution and careful monitoring are recommended when use of these compounds is 
necessary, use of these compounds does not exclude subjects from participating in this trial. 
 
Subjects taking warfarin or other warfarin-derivative anticoagulants should be monitored regularly 
for changes in prothrombin time or INR. 
 
4.5.2 Prohibited Concomitant Therapy 
 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase of this trial:   
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol  
• Chemotherapy not specified in this protocol  
• Investigational agents other than the study drug in this trial  
• Radiation therapy  
 
NOTE: Radiation therapy to a symptomatic solitary lesion may be considered on an exceptional 
case by case basis after consultation with sponsor-investigator. The subject must have clear 
measurable disease outside the radiated field. Administration of palliative radiation therapy will 
be considered clinical progression for the purposes of determining PFS.  
 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the 
trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed. However, intranasal 
influenza vaccines (e.g. Flu - Mist®) are live attenuated vaccines, and are not allowed. 
 
4.6 
Dose Modifications 
 
The National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events Version 4 
(CTCAE) will be used to grade toxicity (http://evs.nci.nih.gov/ftp1/CTCAE/About.html).    
 
4.6.1 Dose Modification Table 
 
See below for modifications of paclitaxel and carboplatin, for adverse events which are possibly, 
probably, or likely due to either drug. 
 
Hematologic Requirements for Day 1 of Each Cycle 
Dose delay based on hematologic counts the day of treatment: The ANC count must be ≥1,500/mcl 
and the platelet count ≥ 100,000/mcl on the day of planned treatment. If this recovery is not 
achieved by the day of treatment, the next cycle will be delayed until recovery occurs or a 
maximum of 2 additional weeks have passed (a total of five weeks since the beginning of the prior 
cycle). If a delay is > 3 weeks based on these parameters, discontinue all three. 
 
 
 


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Dose Level 
Carboplatin (AUC) 
Paclitaxel (mg/m2) 
0 
6 
200 
-1 
5 
175 
-2 
4 
150 
 
If subjects require a dosage reduction of paclitaxel and carboplatin for toxicity, then they will also 
receive a concomitant reduction of the dose of PF-05212384 by one dosing cohort level. Those 
who still experience the same level of toxicity after a dosage reduction will receive a dose decrease 
to the next lowest dosing cohort. If a subject has been dose decreased to the lowest dosing cohort, 
then the will be taken off of protocol therapy, though they may continue to receive paclitaxel and 
carboplatin alone, at their attending physician’s discretion. 
 
Dose Modification: 
Intra-patient dose reduction and dose interruption will be permitted once a subject has experienced 
drug-related toxicity provided that the criteria for subject withdrawal from study treatment have 
not been met. All intra-patient dose reductions are relative to the lowest dose of the current cycle.  
 
There will be no intra-patient dose escalation. Dose adjustments are to be made according to the 
level of toxicity experienced.  Toxicity will be graded using NCI CTCAE (version 4.0.3).  
Treatment may be delayed no more than two weeks to allow recovery from toxicity.  All toxicities, 
unless otherwise specified below, should resolve to grade 1 prior to beginning treatment.  
 
4.6.2 Non- Hematologic Toxicity 
 
Cardiac Toxicity - Carboplatin and Paclitaxel 
If a subject develops chest pain or arrhythmia during the infusion, the infusion should be stopped. 
Manage any arrhythmias according to standard practice. Subjects who experience chest pain 
during paclitaxel infusion should not restart paclitaxel until a cardiac ischemic event has been ruled 
out. Subjects will be removed from paclitaxel and carboplatin treatment in cases of symptomatic 
arrhythmias or AV block (except first degree) or other heart block. In case of first degree AV 
block, subject may continue paclitaxel infusion with continuous cardiac monitoring during the 
infusion, at the discretion of the treating physician. 
 
Hypersensitivity Reactions - Paclitaxel 
Caution: Subjects who have a mild to moderate hypersensitivity reaction should be re-challenged, 
but careful attention to prophylaxis and bedside monitoring of vital signs is recommended. For 
moderate symptoms (e.g., moderate rash, flushing, mild dyspnea, chest discomfort), stop the 
infusion. Give intravenous diphenhydramine 25 mg and intravenous dexamethasone 10 mg. After 
recovery of symptoms, resume infusion at a low rate, 20 mg/hr for 15 minutes. If no further 
symptoms, resume at full dose rate until infusion is complete. If symptoms recur, the infusion will 
be stopped. The subject should receive no additional paclitaxel for that cycle, but may be retreated 
after discussion with the study PI. For severe life threatening symptoms (e.g., hypotension 
requiring pressor therapy, angioedema, respiratory distress requiring bronchodilator therapy, 
generalized urticaria), stop the infusion. Give intravenous diphenhydramine and dexamethasone 
as above. Add epinephrine or bronchodilators if indicated. If wheezing is present that is not 


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responsive to administration of 0.35 cc of nebulized salbutamol solution (or equivalent), 
epinephrine is recommended. The subject will be taken off paclitaxel treatment.  
 
Dose Modifications for Non-Hematologic Toxicities:  
For Grade 3 and 4 toxicities, treatment should be withheld until the toxicity resolves to Grade 1 or 
less (or to baseline), then reinstituted (if medically appropriate) at a one level dose reduction. 
Nausea and vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy. 
All agents should be dose reduced in cases where either agent may be the cause of a given toxicity. 
Subjects must meet pre-treatment laboratory criteria (as specified in the inclusion criteria) at Day 
1 of each cycle to receive therapy administration. Subjects will not be eligible for further treatment 
if resolution of toxicities requires a greater than 3-week delay in the start of the next cycle (five 
weeks from the start of the prior cycle).  
 
4.6.3 Hematologic Toxicity 
 
Dose Modifications for Hematologic Toxicity:  
Grade 1, 2 and 3 myelosuppression (neutropenia, thrombocytopenia), with recovery to pre-
treatment lab criteria as specified in the inclusion criteria, does not require dose modification. 
Grade 3 or 4 lymphopenia does not require dose reduction. Subjects with a febrile Grade 4 
neutropenia >7 days or Grade 4 neutropenia associated with fever (one reading of oral temperature 
> 38.5° C, or three readings of oral temperature > 38.0° C in a 24-hour period) or Grade 4 
thrombocytopenia >7 days should be retreated after recovery at a one-dose level reduction during 
subsequent cycles. If any of these toxicities recurs, the subject should be dose reduced again in all 
subsequent cycles after recovery to pre-treatment lab criteria as specified in the inclusion criteria. 
Subjects will not be eligible for further treatment if resolution of toxicities requires a greater than 
2-week delay in the start of the next cycle. Subjects who need two dose level reductions of 
paclitaxel and carboplatin, or a dose reduction of PF-05212384 to less than Dose Level 1 should 
discontinue from the study.    
 
4.7 
Supportive Care Guidelines 
 
Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, antidiarrheals, analgesics, etc., when appropriate. Bisphosphonates or 
denosumab are allowed for subjects with bone metastases. 
 
In the Phase II portion of this study, prophylactic oral mucositis therapy may be administered with 
an oral steroid rinse and spit agent.  Refer to Section 4.7.1 for the management of oral mucositis 
in the Phase I portion of this study. 
 
4.7.1 Special Warnings and Precautions for Use 
 
Oral Toxicity Management 
 
In the Phase I/dose escalation portion of this protocol, a prophylactic steroid oral rinse and spit 
agent, or any other type of anti-oral mucositis therapy, use should be avoided.  Active therapy 
should be administered at the first prodromal signs of mucositis, i.e.; xerostomia, sensory changes, 


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or any new oral symptoms reported by a subject.  These listed symptoms may precede oral 
ulceration and stomatodynia. 
 
During the Phase II portion of study, with the MTD is established, prophylactic oral mucositis 
therapy may be administered.  An oral steroid rinse and spit agent should be given to subjects; in 
this setting, a magic mouthwash (which includes anesthetic agents) is not the best therapy for oral 
mucositis. 
 
5. TREATMENT DISCONTINUATION 
 
5.1 
Removal of Subjects From Study 
 
Subjects who discontinue participation in the clinical study on their own or subjects who are 
withdrawn by the investigator, for reasons other than completion of treatment, disease progression 
or toxicity, will be defined as premature withdrawals.  
 
Subjects who are not initiated on study drug, but sign informed consent and undergo at least some 
of the screening procedures will be considered screening failures. A record of these subjects will 
be maintained by the study site. 
 
5.2 
Criteria For Study Treatment Discontinuation 
 
A subject will be discontinued from protocol therapy under the following circumstances: 
• Any adverse event which, in the Investigator’s opinion, requires termination of the study 
medication. 
• Disease progression, unless at the discretion of the principal investigator (in collaboration with 
any co-sponsors or collaborators) continued treatment with study drug is appropriate. 
• Substantial non-compliance (>25% of missed doses accounting for delays and dose 
modifications per protocol or instructions from research team staff for AEs), with the 
requirements of the study. 
• The subject presents with a beta-HCG test consistent with pregnancy.  Pregnancy will be 
reported along the same timelines as a serious adverse event. 
• The subject uses illicit drugs or other substances that may, in the opinion of the Investigator, 
have a reasonable chance of contributing to toxicity or otherwise interfering with results. 
• The development of a second malignancy that requires treatment, which would interfere with 
this study. 
• The subject is lost to follow-up. 
• Interruption in study drugs administration for greater than 21 days (see Dose Modification 
section). 
• Development of an intercurrent illness or situation which would, in the judgment of the 
investigator, affect assessments of clinical status and study endpoints to a significant degree. 
 


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The Investigator will make every reasonable effort to keep each subject in the study unless it is in 
the subject’s best interests to discontinue participation.  If a subject is removed from the study or 
declines further participation, all End of Treatment evaluations should be performed if the subject 
is willing and able to be assessed.  A description of the reason(s) for withdrawal from the study 
must be recorded on the case report form (CRF).  The Investigator should also ensure that all 
subjects are followed up for survival status after the Final Visit. 
 
Relevant visit data should be entered on the CRF and any unused study medication will be 
accounted for and returned for all subjects participating in the study, even for a brief period of 
time.  Subjects who discontinue following entry will have relevant information completed and 
recorded on the CRF.  All subjects who discontinue because of adverse events or clinically 
significant laboratory abnormalities should be followed up until they recover or stabilize, and the 
subsequent outcome will be recorded.  If any subject should die during the trial or within 30 days 
of stopping study treatment, the Investigator will inform the UF Health Data Integrity and Safety 
Committee (DISC).   
 
5.3 
Replacement of Subjects 
 
Subjects will be replaced if they have not received any doses of study drug prior to their continuing 
participation in the protocol for any reason, or if the subject wishes to discontinue participation in 
the protocol, but is not discontinued for disease progression, toxicity, or any of the reasons listed 
in section 5.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6. STUDY PROCEDURES 
 
6.1 
Study Schedule of Events 
 
Day of Protocol 
Baseline2 
Day 1, 
Each 
Cycle 
Within 
one 
calendar
week of 
Day 1, 
odd 
cycles 
Day 2, 9, 
16, Each 
Cycle 
Off 
Treatment 
Off 
Study 
Studies: 
 
 
 
 
 
 
H&P1 / PS / VS & TOX 
X 
X 
 
 
X 
X 
CBC w/ Diff. 
X 
X 
 
X4 
X 
X 
CMP 
X 
X 
 
 
X 
X 
UA and Pregnancy Test 
X 
 
 
 
 
 
Diagnostic 
Imaging 
Scan / TA3 
X 
 
X 
 
 
X 
ECG 
X 
 
 
X5 
 
 
Treatment: 
 
 
 
 
 
 
PF-05212384, IV 6 
 
 
 
X 
 
 
Paclitaxel 200 mg/m2 
 
X 
 
 
 
 
Carboplatin AUC = 6 7 
 
X 
 
 
 
 
1) Abbreviations: H&P=History and Physical examination; PS=ECOG performance status; VS=vital signs (blood pressure, 
temperature, pulse and respiratory rates, weight and height); TOX=toxicity assessment; CBC/diff=complete blood count 
and white blood cell differential; CMP=12 item complete metabolic profile (sodium, potassium, chloride, bicarbonate, blood 
urea nitrogen, creatinine, glucose, alkaline phosphatase, AST, ALT, total bilirubin, uric acid); UA=urinalysis; Pregnancy 
test only for women of childbearing potential 
2) Baseline studies are repeated on day 1 if there are more than 14 days between baseline and day 1. The radiographic 
assessment must be repeated if there are more than 21 days between baseline and day 1. 
3) TA= Tumor assessment by RECIST Criteria by diagnostic CT scan and/or MRI scan. 
4) Day 1 and Days 2, 9 and 16 before each PF-05212384 dose 
5) Days 2, 9 and 16 of the first cycle only, after each PF-05212384 dose 
6) Dose is determined by the dosing cohort that the subject is enrolled into 
7) The carboplatin dose (mg) = AUC x (CrCl + 25) where AUC = 6 depending on the dose level. The creatinine clearance 
will be calculated using a serum creatinine obtained within 3 days prior to each dose. Carboplatin dose will be based on 
GFR* (glomerular filtration rate) based on the measurement of creatinine clearance where GFR is calculated using the 
Cockroft-Gault Formula: 
CrCI = [(140 - age) x actual body weight (kg)**] / [72 x serum creatinine***] 
Multiply this number by 0.85 if the subject is female. 
 
* GFR = calculated creatinine clearance determined using the Cockroft-Gault Formula based on age, weight (actual body 
weight) and serum creatinine. 
** Use current (actual) weight. This should be actual weight but not exceed 140% of IBW. 
*** In subjects whose serum creatinine is < 0.8 mg/dl, 0.8 mg/dl must be substituted in the Cockroft-Gault formula to 
calculate the estimated creatinine clearance for carboplatin dosing. 
Please note that: GFR should not exceed 125 m/min. Hence, the maximum total carboplatin dose should NOT exceed 900 
mg. 
****Follow up evaluations are also performed as appropriate clinically 
 


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6.2 
Screening Evaluations   
 
Written informed consent must be obtained prior to performing any study-specific evaluations or 
tests. Tests or evaluations performed as standard of care within the specified screening period, but 
prior to informed consent, may be accepted for this study and need not be repeated. 
 
Pretreatment measurements (to be completed within 21 days prior to initiation of therapy): 
a. Height, weight and performance status 
b. Physical exam 
c. Laboratory studies:  
 
 
CBC with leukocyte differential count 
 
 
Comprehensive metabolic panel (CMP) 
 
 
Urine pregnancy test (females of potential child-bearing status only) 
Plain films, CT or PET/CT scans, or MRI scans used for tumor measurement 
 
6.3 
On-Study Evaluations  
 
Prior to initiating each treatment cycle: 
 
a. Toxicity assessment, interim medical history and physical examination 
b. Laboratory studies:  
CBC with leukocyte differential count 
CMP 
Prior to initiating every other treatment cycle: 
CT, PET/CT or MRI scans to document tumor status. 
 
6.4 
End of Treatment 
 
Subjects should be seen in the clinic or contacted by telephone to determine if any serious or non-
serious adverse events have occurred within 28 days (+ 3 days) of termination of PF-05212384 
dosing. 
 
Follow-up Evaluation 
Subjects will be followed for 28 days after completion of the last course of any therapy for the 
documentation of adverse events.  
 
Off-therapy measurements: 
a. Toxicity assessment, interim medical history and physical examination 
b. Laboratory studies: 
 
 
CBC with differential count 
 
CMP 
 
6.5 
Follow up/Survival 
 
Subjects will be seen in follow-up at least every three months for the first year after the initiation 
of therapy or until disease progression, or the date of death. Evaluation will consist of an interim 
medical history and a physical examination. Additional studies, such as labs (CBC and CMP), and 


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any X-rays, or CT, PET/CT, bone scans or MRI scans used in evaluation of response will be 
repeated as clinically indicated.  Other studies, such as, biopsies, will be performed as clinically 
indicated. 
 
7. CRITERIA FOR DISEASE EVALUATION 
 
7.1 
Defintions 
 
Evaluable for toxicity.  All subjects will be evaluable for toxicity from the time of their dose of 
any of the three drugs in this study. 
 
Evaluable for objective response.  Only those subjects who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These subjects will have their response classified according 
to the definitions stated below.  (Note:  Subjects who exhibit objective disease progression prior 
to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Subjects who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm 
with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area are considered measurable 
only if they have demonstrated growth after completion of the radiation therapy.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 


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Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 


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than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
 
Endoscopy or Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Tumor Markers. Tumor markers alone cannot be used to assess response.  There are no validated 
tumor markers for NSCLC, and none are being evaluated here. 
 
Cytology or Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 


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mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
7.2 
Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 


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Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a subject 
to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The subject’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Subjects with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 


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***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
  
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
8. ADVERSE EVENTS 
 
8.1 
Definitions 
 
8.1.1 Adverse Event 
 
The term “adverse event” includes any sign, symptom, syndrome, or illness that appears or 
worsens in a subject during the period of observation in the clinical study and that may impair the 
wellbeing of the subject. The term also covers laboratory findings or results of other diagnostic 
procedures that are considered to be clinically significant (e.g., that requires unscheduled 
diagnostic procedures or treatment measures, or result in withdrawal from the study). 
 


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The adverse event may be: 
• A new illness/condition; 
• Worsening of a sign or symptom of the condition under treatment, or of a concomitant 
illness/condition; 
• An effect of the study drug; or 
• A combination of 2 or more of these factors. 
 
No causal relationship with the study drug or with the clinical study itself is implied by the use of 
the term “adverse event.” 
 
Surgical procedures themselves are not adverse events; they are therapeutic measures for 
conditions that require surgery. The condition(s) for which the surgery is required may be an 
adverse event. Planned surgical measures permitted by the clinical study protocol and the 
condition(s) leading to these measures are not adverse events. 
 
When a clear diagnosis is available that explains the abnormal objective findings, this diagnosis 
will be recorded as an adverse event and not the abnormal objective findings (e.g., viral hepatitis 
will be recorded as the adverse event and not the transaminase elevation). If a definitive diagnosis 
is not available, then the sign(s) (e.g., clinically significant elevation of transaminase levels) or 
symptom(s) (e.g., abdominal pain) will be recorded as the adverse event. 
Adverse events fall into the categories “serious” and “non-serious.” 
 
8.1.2 Serious Adverse Event 
 
A serious adverse event is one that at any dose of the study drug or at any time during the period 
of observation: 
• Results in death 
• Is life-threatening (defined as an event in which the subject 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 causes prolongation of existing hospitalization (see 
note below for exceptions) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event, defined as a medical event that may not be immediately life-
threatening or result in death or hospitalization but, based on appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed above. Examples of such 
events include but are not limited to intensive treatment in an emergency department or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization. “Medically important” should be marked only if no other serious criteria 
are met. 
 
An “unexpected SAE” is any SAE for which the nature, specificity or severity is not consistent 
with the currently known adverse event profile of the investigational agent(s). 


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NOTE: The following hospitalizations are not considered SAEs in UFHCC clinical studies: 
• a visit to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a 
life-threatening event) 
• elective surgery planned before signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 
• medical/surgical admission for purpose other than remedying ill health state that was 
planned before study entry. Appropriate documentation is required in these cases. 
• admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative). 
 
Clarification of the difference in meaning between “severe” and “serious” 
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). Any grade ≥ 3 adverse event per CTCAE is 
generally considered severe AE. This is not the same as “serious,” which is based on the outcome 
or action criteria usually associated with events that pose a threat to life or functioning. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
8.1.3 Non-Serious Adverse Event 
 
A non-serious adverse event is any adverse event not meeting any of the serious adverse event 
criteria. 
 
8.2 
Period of Observation 
 
Following the subject’s written consent to participate in the study, all SAEs must be collected, 
including those thought to be associated with protocol-specified procedures. Collection of all SAEs 
must continue for 30 days after the last administration of the investigational product. If applicable, 
SAEs must be collected that relate to any later protocol-specified procedure (e.g., a follow-up skin 
biopsy). The investigator should notify the DISC of any SAE occurring after this time period that 
is believed to be related to the investigational product or protocol-specified procedure. 
 
The investigator will begin collecting non-serious adverse event (NSAE) information once 
administration of the investigational product is initiated. This NSAE information should also be 
collected from the start of a placebo lead-in period or other observational period intended to 
establish a baseline status for the subjects.  Treated subjects, including those who were prematurely 
discontinued from the study, will be followed for any adverse events that occur during the study 
until 28 days following the last dose of study treatment (i.e., the Follow-up Visit).  However, if 
another course of anti-cancer therapy is initiated prior to the 28-day follow-up period visit, 
collection of adverse events will no longer be performed, with the exception of events that may be 
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8.3 
Documenting and Reporting of Adverse Events by Investigator 
 
All adverse events must be fully recorded in the subject’s case record form. 
 
Documentation must be supported by an entry in the subject’s file.  A laboratory test abnormality 
considered clinically relevant, e.g., causing the subject to withdraw from the study, requiring 
treatment or causing apparent clinical manifestations, or judged relevant by the investigator, 
should be reported as an adverse event.  Each event should be described in detail along with start 
and stop dates, severity, relationship to investigational product, action taken and outcome. 
 
Every attempt should be made to describe the adverse event in terms of a diagnosis that 
encompasses the component signs and symptoms. If only nonspecific signs or symptoms are 
present, then these should be recorded as separate diagnoses on the pages of the case report form. 
 
All subjects who have adverse events, whether considered associated with the use of study drug 
or not, must be monitored to determine the outcome. The clinical course of the adverse event will 
be followed according to accepted standards of medical practice, even after the end of the period 
of observation, until a satisfactory explanation is found or the Principal Investigator considers it 
medically justifiable to terminate follow-up. Should the adverse event result in death, a full 
pathologist’s report should be supplied, if possible. 
 
8.3.1 Assessment of Causal Relationship to Study Drug 
 
The Investigator will provide an assessment of the potential causal relationship between adverse 
events and study medication by determining whether or not there is a reasonable possibility that 
the event was caused by the study medication. The relationship or association of the adverse event 
to the study medication will be characterized as not related, probably not related, possibly related, 
probably related, or related:   
 
Not Related: There is not a temporal relationship to the study drug administration or the adverse 
event is clearly due only to the progression of the underlying disease state, intercurrent illness, 
concomitant medication, concurrent therapy or other known cause. 
 
Probably Not Related:  There is little or no chance that the study drug administration caused the 
adverse event; the event is most likely due to another competing cause, including intercurrent 
illness, progression or expression of the disease state, or a reaction to a concomitant medication or 
concurrent therapy appearing to explain the reported adverse event.  
 
Possibly Related:  The association of the adverse event with the study drug administration is 
unknown; however, the adverse event is not reasonably attributed to any other condition.  
 
Probably Related:  When a reasonable temporal relationship exists between the adverse event 
and the study drug administration; significant symptoms abate upon discontinuation of the study 
drug and there is a reasonable explanation based on known characteristics of the study drug and 
there is no clear association with preexisting disease or therapy, intercurrent illness, concurrent 


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therapy or other factor(s). 
 
Related:  When the adverse event is a known side effect of the study drug or there is a temporal 
relationship to the administration of the study drug; or the adverse event reappears upon re-
administration of the study drug (rechallenge); or the significant symptoms of the adverse event 
abate upon discontinuation of the study drug (dechallenge). 
 
8.3.2 Intensity of Adverse Events 
 
The intensity of adverse changes in physical signs or symptoms will be graded according to the 
CTCAE version 4. For all other adverse events not described in the CTCAE, the intensity will be 
assessed by the Investigator using the following categories: 
 
Mild (Grade 1) – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
 
Moderate (Grade 2) – mild to moderate limitation in activity, some assistance may be needed; no 
or minimal medical intervention/therapy required. 
 
Severe (Grade 3) – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible. 
 
Life-threatening (Grade 4) – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable. 
 
Death (Grade 5) – the event resulted in death. 
 
8.3.3 Action Taken with Study Drug 
 
The action the Investigator took with study drug as a result of the event should be recorded as one 
of the following: 
 
None – No action was taken with regard to the study drug as a result of the adverse event. 
 
Interrupted – Study drug was stopped due to the adverse event, but was later resumed at the same 
dose. 
 
Dose decreased – The dose of study drug was decreased as a result of the adverse event. 
 
Permanently discontinued – The subject was withdrawn from the study due to the adverse event. 
 
Only one item should be chosen. If multiple actions apply, the following “worst case” scenario 
hierarchy should be used to determine the preferred entry: 
 
Discontinued > dose decreased > therapy interrupted. 
 


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8.3.4 Definition of Outcome 
 
The outcome of the AE should be recorded as one of the following: 
 
Resolved without sequelae – The subject fully recovered from the adverse event with no 
observable residual effects. 
 
Resolved with sequelae – The subject recovered from the adverse event with observable residual 
effects. 
 
Not resolved – The adverse event was present at the time of last observation. 
 
Death – The subject died as a result of the adverse event. 
 
8.4 
Immediately Reportable Events 
 
8.4.1 Serious Adverse Events 
 
For Pfizer reporting requirements, all SAEs, as well as exposure during pregnancy, must be 
reported to the Pfizer U.S. Clinical Trial Department or designee within 24 hours of awareness.  
SAEs will be reported to Pfizer via fax at (866) 997-8322.  A Pfizer Investigator Initiated Research 
Serious Adverse Event Report Form must be used to document and communicate the event to 
Pfizer.  In the event an embryo or fetus has been exposed to the investigational agent, a Pfizer 
Exposure During Pregnancy (EDP) Supplement Form must accompany the Investigator Initiated 
Research Serious Adverse Event Report Form.  All event reports are to be faxed with the Pfizer 
Reportable Event Fax Cover Sheet (US). 
 
For UFHCC SAE reporting requirements the FDA MedWatch 3500A form is the required form 
for internal submissions.  In addition to completing appropriate subject demographic and suspect 
medication information, the report should include the following information within the Event 
Description of the MedWatch 3500A form: 
 
1. Treatment regimen (dosing frequency, combination therapy) 
2. Protocol description (and number, if assigned) 
3. Description of event, severity, treatment, and outcome, if known 
4. Supportive laboratory results and diagnostics 
5. Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Follow-Up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
 


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Summarizing new information and faxing it with a cover letter including subject identifiers (i.e. 
D.O.B., initials, subject number), protocol description and number, if assigned, suspect drug, 
brief adverse event description, and notation that additional or follow-up information is being 
submitted  (The subject identifiers are important so that the new information is added to the 
correct initial report.)  MedWatch 3500A forms may be reported to the FDA by phone at (800) 
332-1088, via fax at (800) 332-0178, or online at www.fda.gov/medwatch/report.htm. 
 
UF DISC Reporting Requirements 
 
Serious adverse events (SAE's) must be documented on a SAE Report Form must be emailed to 
the UFHCC DISC Safety Team within 5 days of discovery of the event. The original copy of the 
SAE Report and any email correspondence must be kept within the Trial Master File at the study 
site. The site investigator is responsible for informing the IRB and/or the Regulatory Authority of 
the SAE as per local requirements.  
 
Follow-up information will be emailed or faxed to the UFHCC using the SAE Report Form stating 
that this is a follow-up to the previously reported SAE and giving the date of the original report. 
Each re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not (if applicable), and whether the participant continued or withdrew from study 
participation. 
 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
 
 
8.4.2 Other Events Requiring Immediate Reporting 
 
All pregnancies, regardless of outcome, must be reported to the UFHCC DISC, including 
pregnancies that occur in the female partner of a male study subject. All pregnancies must be 
followed to outcome. 
 
Although overdose (dose variance of >25%) and cancer are not always serious by regulatory 
definition, these events should also be reported to the DISC in an expedited manner.  In case the 
overdose did not result in any adverse event, the Investigator should report this as “overdose, no 
adverse event” on the SAE form and provide the intended amount, as well as the actual amount, 
of drug administered.  In the event of overdose or exaggerated response, appropriate supportive 
measures should be employed.  Actual treatment should depend on the severity of the clinical 
situation and the judgment and experience of the treating physician. 
 
Pregnancies and overdoses should be documented and reported per the SAE reporting guidelines 
in section 8.4.1 above. 
 
 
 


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8.5 
IND Safety Reports Unrelated to this Trial 
 
IND safety reports not occurring on this trial but involving the study intervention (outside SAEs) 
received from outside sources will be forwarded to participating sites for submission to their 
Institutional Review Boards per their guidelines.  
 
9. STATISTICAL METHODS 
 
The sections below provide an overview of the statistical considerations and analyses. 
 
9.1 
Study Objectives 
 
9.1.1 Primary 
 
• To identify the maximum tolerated dose of PF-05212384 in combination with paclitaxel and 
carboplatin in subjects with NSCLC (Phase Ib) 
• To document the response rate of subjects with NSCLC receiving PF-05212384 with paclitaxel 
and carboplatin, according to current RECIST criteria (Phase II) 
 
9.1.2 Secondary 
 
• To document the severity and reversibility of toxicities 
• To estimate median duration of response 
• To estimate progression-free survival for subjects on this trial with NSCLC treated with PF-
05212384 in combination with paclitaxel and carboplatin 
• To estimate the overall survival of subjects with NSCLC receiving PF-05212384 with 
paclitaxel and carboplatin 
 
9.2 
Sample Size Determination 
 
The trial will enroll 41 total subjects, 12 in the phase Ib portion and up to 29 in the phase II portion.  
In the phase II portion of the study, so we are interested in evaluating the feasibility and safety of 
a regimen of weekly PF-05212384 in combination with paclitaxel and carboplatin administered to 
subjects with non-small cell lung cancer. To minimize the number of subjects exposed, the sample 
size will be determined by the anticipated response rate. A response rate of 20% or above to PF-
05212384 in combination with paclitaxel and carboplatin will be of interest in subjects with 
previously-treated squamous cell lung cancer. To determine the appropriate sample size with an 
overall type I error of 0.05 and power 0.8, Simon's two-stage design (Simon, 1989) is used. The 
null hypothesis that the true response rate is 0.05 is tested against a one-sided alternative that the 
true response rate is bigger than 0.2. In the first stage, 10 subjects will be accrued. If there are no 
responses among these 10 subjects, the study will be stopped. Otherwise, 19 additional subjects 
will be accrued for a total of 29. The null hypothesis will be rejected if 4 or more responses are 
observed in 29 subjects. This design yields a type I error rate of 0.047 and power of 0.8 when the 
true response rate is 0.2. A subject is considered eligible for toxicity evaluation if they have 


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received at least one dose of PF-05212384, paclitaxel or carboplatin. A subject will be considered 
eligible for evaluation of activity if they have also received two cycles of therapy as planned. 
 
The phase Ib portion of the study will utilize a 3+3 dose escalation design using the dose 
levels of PF-05212384 listed in the table below.  The doses for paclitaxel (200 mg/m2, Q21 
days) and carboplatin (AUC=6, Q21 days) do not adjust as part of the study design. 
 
Dose Cohort 
PF-05212384 Dose (mg, days 2, 9, 16) 
1 
110 
2 
150 
3 
180 
 
During the first stage, cohorts of 3 participants each will be sequentially enrolled to each 
increasing dose level, beginning with dose level 2 (150mg) until the first dose limiting 
toxicity occurs.  Once that happens, the first stage will end and the trial will move to the 
second stage.  During the second stage, 10 subjects will be evaluated for response, and if none 
of the 10 evaluable subjects experiences a partial or complete response, then the study will be 
terminated. Otherwise, 19 additional subjects will be accrued for a total of 29. The null hypothesis 
will be rejected if 4 or more responses are observed in 29 subjects. 
 
9.3 
Statistical Analysis Plan 
 
The maximum tolerated dose of PF-05212384, in combination with paclitaxel and carboplatin, 
will be determined by the dose escalation rules summarized in Sections 4.2 and 9.2.  All subjects 
who received study drug will be included in the safety analysis of this combination regimen. 
Adverse event data and corresponding toxicity grades during treatment and during long-term 
follow-up will be summarized in the form of tables. Incidence tables will be generated to 
summarize incidence of subjects reporting at least one episode of each specific adverse event, 
incidence of adverse events causing withdrawal and incidence of serious adverse events. The total 
number of episodes for each event reported (Frequency Table), the severity and attribution to study 
therapy of each episode reported (Severity Table and Attribution Table) will also be displayed.  
Listings of adverse events by subjects will include the time to onset, the duration of each event, 
the severity of each event, and the relationship of the event to study therapy, whether it was a 
serious event, and whether it caused withdrawal. Safety data will be summarized for the overall 
subject group and by dose levels. Dose-toxicity curves will be fitted to the final data to estimate 
the toxicity rates of each dose levels.    
 
9.4 
Efficacy Analysis 
 
The primary endpoint of the phase Ib portion of this protocol is to determine a tolerable phase II 
dose of PF-05212384 in combination with paclitaxel and carboplatin. The primary endpoint of the 
phase II portion of this study is to determine the objective response rate of disease to the 
administration of PF-05212384 in combination with paclitaxel and carboplatin. A secondary 
endpoint of this study will be progression-free survival following PF-05212384 therapy.  Kaplan-
Meier mean estimates and survival curves of progression-free survival rates will be calculated. 


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Secondary endpoints, including response rates, clinical benefit rate (CR + PR + SD), toxicities and 
reversibility of toxicities, will be estimated along with exact 95% binomial confidence intervals. 
 
9.5 
Analysis of Demographic and Baseline Characteristics 
 
The analysis of demographic characteristics (age, gender, tobacco abuse history and 
ethnicity) and baseline characteristics, including weight, performance status, and histologic 
subtype, will be primarily descriptive. They will be summarized in tabular format. 
 
9.6 
Analysis of Safety Data 
 
Subjects will be examined and graded each cycle for subjective/objective evidence of 
developing toxicity according to NCI-CTC toxicity criteria.  Toxicities will be graded 
according to Common Toxicity Criteria (CTCAE) v4.03.  Incidence tables will be generated to 
summarize incidence of subjects reporting at least one episode of each specific adverse 
event, incidence of adverse events causing withdrawal, and incidence of serious adverse 
events. 
 
In the absence of significant treatment-related abnormalities, in subsequent courses subjects 
will not require weekly laboratory evaluation, but will require the documentation of return 
to baseline values prior to the initiation of subsequent courses of therapy. 
 
10. DATA AND SAFETY MONITORING 
 
10.1 Data Integrity and Safety Committee 
 
This protocol will be reviewed and monitored by the University of Florida Health Cancer Center 
(UFHCC) Data Integrity and Safety Committee (DISC) in accordance with their policies and 
procedures.  They will review and monitor study progress, toxicity, safety and other data from this 
trial. Questions about subject safety or protocol performance will be addressed with the sponsor-
investigator, statistician and study team members. Should any major concerns arise; the DISC will 
offer recommendations regarding whether or not to suspend the trial. 
 
UFHCC DISC data and safety monitoring activities include:  
• Review of clinical trial conducted for progress and safety  
• Review of all adverse events requiring expedited reporting as defined in the protocol  
• Review of reports generated by data quality control review process  
• Notification of the sponsor-investigator of recommended action  
• Notification of sites coordinated by the UFHCC of adverse events requiring expedited 
reporting and subsequent committee recommendations for study modifications 
 
 
 
 


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10.2 On-Site Monitoring 
 
UFHCC monitors will make monitoring visits to the trial sites periodically during the trial to 
determine if sites are complying with the protocol. Source documents will be reviewed for 
verification of agreement with data as submitted via the data collection system. The site 
investigator/institution guarantee access to source documents by UFHCC or its designee and 
appropriate regulatory agencies.   
 
The trial site may also be subject to quality assurance audit by any collaborating sponsors or their 
designee as well as inspection by appropriate regulatory agencies.  
 
It is important for the site investigator and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
 
10.3 Principal Investigator Responsibilities 
 
As part of the responsibilities assumed by conducting this study, the Principal Investigator (PI) 
agrees to maintain and have available for monitoring adequate case records (accurate source 
documents and CRFs) for the subjects treated under this protocol.  
 
The PI will be primarily responsible for monitoring of adverse events, protocol violations, and 
other immediate protocol issues. The study coordinator will collect information on subjects 
enrolled through the use of electronic or paper adverse event (AE) forms, CRFs, and Informed 
Consent forms.  
 
11. EMERGENCY PROCEDURES 
 
11.1 Emergency Contact 
 
In emergency situations, the treating physician should contact the Principal Investigator by 
telephone at the number listed on the title page of the protocol 
. 
11.2 Emergency Identification of Investigational Products 
 
This is an unblinded, nonrandomized study. Thus, there will be no need for unmasking 
procedures, and the identification of the investigational product can be made by simple inquiry to 
the investigational pharmacy. 
 
11.3 Emergency Treatment 
 
During and following a subject’s participation in the study, the treating physician and/or institution 
should ensure that adequate medical care is provided to a subject for any adverse events, including 
clinically significant laboratory values, related to the study. 
 
 


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12. ADMINISTRATIVE CONSIDERATIONS 
 
12.1 Good Clinical Practice 
 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Principal Investigator and Co-
Investigators abide by Good Clinical Practice (GCP), as described in International Conference on 
Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki.  
 
The study will be conducted in compliance with the protocol. The protocol, any amendments, and 
the subject informed consent will receive Institutional Review Board (IRB) approval before 
initiation of the study.  
 
The Principal Investigator will conduct all aspects of this study in accordance with applicable 
national, state, and local laws of the pertinent regulatory authorities. 
 
All potential serious breaches must be reported to the UF Health Cancer Center Data Integrity and 
Safety Committee (DISC) immediately. A serious breach is a breach of the conditions and 
principles of GCP in connection with the study or the protocol, which is likely to affect, to a 
significant degree, the safety or physical or mental integrity of the subjects of the study or the 
scientific value of the study. 
 
12.2 Institutional Review Board 
 
Before study initiation, the investigator must have written and dated approval from the IRB for the 
protocol, consent form, subject recruitment materials/process (e.g., advertisements), and any other 
written information to be provided to subjects. The investigator should also provide the IRB with 
a copy of the Investigator Brochure or product labeling, information to be provided to subjects, 
and any updates. The investigator should provide the IRB with reports, updates, and other 
information (e.g., amendments, and administrative letters) according to regulatory requirements or 
institution procedures. 
 
12.3 Delegation of Investigator Responsibilities 
 
The Principal Investigator will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, the study treatments, and their study-
related duties and functions. The Principal Investigator will maintain a list of Co-Investigators and 
other appropriately qualified persons to whom he has delegated significant study-related duties.  
 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. This study will not use the services of study personnel 
where sanctions have been invoked or where there has been scientific misconduct or fraud (e.g., 
loss of medical licensure; debarment). Systems with procedures that ensure the quality of every 
aspect of the study will be implemented. 
 


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12.4 Subject Information and Informed Consent 
 
Before being enrolled in this clinical trial, the subject must consent to participate after the nature, 
scope, and possible consequences of the clinical study have been explained in a form 
understandable to him or her. An informed consent document that includes both information about 
the study and the consent form will be prepared and given to the subject. This document will 
contain all ICH, GCP, and locally required regulatory elements. The document must be in a 
language understandable to the subject and must specify the person who obtained informed 
consent. 
 
After reading the informed consent document, the subject must give consent in writing. The written 
informed consent will be obtained prior to conducting any study-related procedures or tests. The 
subject’s consent must be confirmed at the time of consent by the personally dated signature of the 
person conducting the informed consent discussions. A copy of the signed consent document must 
be given to the subject. 
 
The PI will retain the original signed consent document. The PI will not undertake any measures 
specifically required only for the clinical study until valid consent has been obtained. 
 
12.5 Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual.   
 
Subjects will be told that the IRB, UF Health Cancer Center Data Integrity and Safety Committee, 
or regulatory authorities may inspect their medical records to verify the information collected, and 
that all personal information made available for inspection will be handled in strictest confidence 
and in accordance with local data protection law. 
 
12.6 Protocol Amendments 
 
Once the study has started, amendments should be made only in exceptional cases. The changes 
then become part of the study protocol. 
 
 
12.7 Case Report Forms 
 
An electronic case report form (eCRF) is required and must be completed for each included 
subject. The completed dataset is the sole property of UFHCC and should not be made available 
in any form to third parties, except for authorized representatives of appropriate Health/Regulatory 
Authorities, without written permission from UFHCC. 
 


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12.8 Record Retention 
 
Study documentation includes all eCRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed subject consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator. In the case of a study with 
a drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
 
UF Health Cancer Center requires that all study documentation be maintained for at least 6 years 
from the date of final study publication.  No study records may be destroyed without prior 
authorization from UF. 
 
 
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APPENDIX 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.