Clinical trial NCT01920061
Conditions: Neoplasm
Keywords: Advanced cancer solid tumors PI3K mTOR PI3K/mTOR metastatic Triple Negative Breast Cancer (TNBC)
Sponsor: Pfizer
Start date: 2013-09-10; Completion date: 2020-01-08
Enrollment: 110 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will evaluate PF-05212384 (gedatolisib) PI3K/mTOR inhibitor)) in combination with either docetaxel, cisplatin or dacomitinib in select advanced solid tumors. The study will assess the safety, pharmacokinetics and pharmacodynamics of these combinations in patients with advanced cancer in order to determine the maximum tolerated dose in each combination. The cisplatin combination expansion portion will evaluate the anti tumor activity of PF 05212384 plus cisplatin in patients with TNBC in 2 separate Arms (Arm 1 and Arm 2).

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: PF-05212384 (gedatolisib) intervention 2: Docetaxel intervention 3: Cisplatin intervention 4: Dacomitinib
Intervention descriptions: intervention 1: PF-05212384 weekly intravenous infusions starting at 90 mg/wk as a 3 week cycle intervention 2: Docetaxel intravenous infusions once every 3 weeks starting at 75 mg/m\^2 intervention 3: Cisplatin intravenous infusions once every 3 weeks starting at 75 mg/m\^2 intervention 4: Dacomitinib to be taken orally as a continuous once daily regimen at a starting dose of 30 mg

Protocol documents:
Prot_000.pdf: 
PF-05212384 (gedatolisib); PF-00299804
B2151002
Final Protocol Amendment 5, 11 November 2016
PFIZER CONFIDENTIAL
Page 1
A PHASE 1B OPEN-LABEL THREE-ARM MULTI-CENTER STUDY TO ASSESS 
THE SAFETY AND TOLERABILITY OF PF-05212384 (PI3K/MTOR INHIBITOR) 
IN COMBINATION WITH OTHER ANTI-TUMOR AGENTS
Compound:
PF-05212384 (gedatolisib); 
PF-00299804
Compound Name:
Gedatolisib; 
Dacomitinib
US IND Number:
European Clinical Trial Database 
(EudraCT) Number:
2013-001390-24
Protocol Number:
B2151002
Phase:
1b
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
&&,
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Document History
Document
Version Date
Summary of Changes
Amendment 5
11 November 2016
The purpose of the amendment was to: 
Include rationale and description of a two arm 
expansion in patients with PF-05212384 in 
combination with cisplatin in adult woman with 
metastatic or locally-recurrent/advanced triple 
hormone-receptor negative breast cancer (TNBC) 
in first- through third-lines of therapy.
Add collection of Patient Reported Outcome (PRO) 
questionnaires for patients enrolled in the 
expansion.
Add collection of Circulating Tumor Cells at 
screening for patients enrolled in the expansion.
Administrative, editorial and typographical updates 
were made.
Amendment 4
15 July 2015
The purpose of the amendment was to: 
Include reference to the generic name for 
PF-05212384 in the header and protocol title page.
Protocol Summary, Study Design, Section 3. Study 
Design and Section 9.3 Sample Size Determination:
•
Modify language due to typographical 
errors that were made when protocol 
Amendment 3 was implemented.  
•
Add language regarding the Pfizer decision 
on April 1, 2015 to stop enrolment in 
Arms A and C of the B2151002 clinical 
trial.  The decision is based on the 
company’s change in prioritization for the 
portfolio and is not due to any safety 
concerns or regulatory interactions.
Schedule of Activities, Footnote 17
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•
Modify tumor assessment schedule for 
patients that remain on study for >12 cycles 
from every 6 weeks (±5 days) to every 
9 weeks (±5 days) to decrease the burden on 
the patients and sites while still ensuring 
adequate monitoring for safety and efficacy. 
Schedule of Activities, Footnote 23
•
Additional language to clarify that 
collection of archival tissue post 
announcement of Pfizer’s decision to close 
Arm A and C is at the discretion of the 
investigator.  In addition, in the event 
archival tissue is not available, a fresh 
biopsy is no longer required.
Section 4.1 Inclusion Criteria, #4 and Section 6.1. 
Screening
•
Added reference to Footnote 23 regarding 
collection of archival tissue.
•
Specify that ovarian cancer (OC) patients 
can be enrolled in Arm B as cisplatin is 
indicated in OC patients. 
Section 4.2. Exclusion Criteria, #8 and 
Section 5.4.1 Drugs Interacting with CYP3A4
•
Removed aprepitant from list of 
exclusionary medications at study entry and 
on study.  The use of “aprepitant” is 
classified as a moderate CYP3A4 inhibitor 
and is permitted in the event that an 
alternative anti-emetic cannot be utilized.
Section 4.3. Life Style Guidelines
•
An administrative clarification to include 
the investigator’s designee per Pfizer’s 
modified protocol template language.
Section 5.2.3.1 PF-05212384
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•
Added language to allow for the possibility 
that an infusion could exceed the protocol 
defined 30 minutes. This is permitted in the 
event of allergic/infusion reactions, and
investigators should institute treatment 
measures according to best medical and 
nursing practice and the infusion time can 
be extended to a maximum of 60 minutes.
Section 5.2.4 Medication Errors
•
Updates made per Pfizer protocol template 
updates.
Section 8 Adverse Event Reporting
•
Updates made per Pfizer protocol template 
updates.
Section 9.1 Analysis Sets
•
Text was added to describe how PK 
samples will be handled when the infusion 
time exceeds the planned 30 minute 
infusion time. This text is necessary since 
the protocol will allow for the infusion to be 
extended in the event of an infusion related 
reaction. 
Section 15.1 Publication of Study Results
•
Updates made per Pfizer protocol template 
updates.
Appendix 9. Management of Allergic Reactions or 
Anaphylaxis.
•
An appendix was added to provide further 
guidance on management of infusion related 
reactions.
Amendment 3
27 May 2014
The purpose of the amendment was to: 
• Include additional dose levels to be tested in 
each study Arm. 
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• Patients who are tolerating treatment at the 
lower dose levels to escalate to the next highest 
dose at which safety/tolerability has already 
been established in the study. 
• Clarifications were made to pharmacokinetic 
sampling and treatment tables to include 
dosing after Cycle 7.
• Clarifications were made to eligibility criteria 
with respect to QT/QTc prolongation.
• Modifications were made to the Sample size 
for each arm due to the addition of dose levels.
Amendment 2
07 October 2013
The primary purpose of the amendment is to 
incorporate feedback based on Health Authority 
feedback.  In addition, modifications were made to 
allow for the use of luteinizing-hormone-releasing 
hormone and low dose steroids for patients that 
have castrate resistance prostate cancer in Arm A 
and clarifications were made to several exclusion 
criteria. 
Amendment 1
10 June 2013
•
Revise US IND Number. 
•
Remove PK sample collected at Baseline.
•
Add two additional ECG collection timepoints 
in Arms A and B to better match the schedule 
with Arm C.
•
Administrative Changes.
Original 
protocol
27 March 2013
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review board (IRB)/external review board
(ERB), etc.  
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PROTOCOL SUMMARY
Rationale:
Signaling through the (phosphatidylinositol 3-kinase) PI3K pathway is associated with 
resistance to a variety of anti-tumor agents.  This has been described pre-clinically with 
cytotoxic chemotherapeutic agents with varying mechanisms of action including taxanes, and 
(deoxyribonucleic acid) DNA-damaging agents.  In the clinic, activated PI3K pathway in 
tumors has been correlated with decreased response to therapy and worse clinical outcomes.
In addition to resistance to cytotoxic agents, there is also evidence of PI3K signaling 
affecting sensitivity of cells to epidermal growth factor receptor (EGFR) family signaling 
inhibitors.  Specifically, the activation of PI3K in tumors has been associated with a worse 
outcome in patients with HER2-positive gastric cancer treated with anti-HER2 agents. In 
addition, pre-clinical studies have described the role of the PI3K pathway in EGFR activation 
in glioblastoma multiforme (GBM) and non-small cell lung cancer (NSCLC) cells and have 
demonstrated that PI3K inhibitors can reverse resistance to EGFR inhibitors in tumor 
models.
Collectively, these findings suggest that PI3K/mammalian target of rapamycin (mTOR)
inhibitors may increase the efficacy of both chemotherapeutic agents which are considered 
standard of care (SOC) for the treatment of several solid tumors and dacomitinib which has 
shown clinical activity in several tumor types.  
Objectives: Original Protocol through Amendment 4
Primary Objective
•
To assess the safety and tolerability and to estimate the maximum tolerated dose 
(MTD) of the following combinations in patients with advanced solid tumors:
•
Arm A: PF-05212384 and docetaxel.
•
Arm B: PF-05212384 and cisplatin.
•
Arm C: PF-05212384 and dacomitinib.
Secondary Objectives
•
To evaluate the overall safety profile.
•
To assess the effects of PF-05212384 on the pharmacokinetics (PK) of docetaxel, 
cisplatin and dacomitinib and vice versa in Arms A, B, and C respectively.
•
To evaluate possible biomarkers of efficacy (eg, KRAS mutation) and 
pharmacodynamic (PD) effects in paired tumor biopsies (eg, pAkt levels) and serum 
(eg, insulin levels).
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•
To characterize the effects of the combinations on the potential to prolong the QTc
interval.
•
To document anti-tumor activity.
Endpoints: Original Protocol through Amendment 4
Primary Endpoint
•
Dose Limiting Toxicity (DLT).
Secondary Endpoints
•
Adverse Events as characterized by type, frequency, severity (as graded by National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
v.4.03), timing, seriousness and relationship to study therapy.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
•
Vital sign abnormalities.
•
Single and multiple dose pharmacokinetic (PK) parameters of PF-05212384, and 
other anti-tumor agents (docetaxel, cisplatin or dacomitinib) alone and together, 
respectively.
•
Gene sequence data (eg, PIK3CA, KRAS) and levels of PI3K pathway protein 
biomarkers (eg, pAkt, PTEN, circulating insulin).
•
QTc interval.
•
Objective tumor response, as assessed using the Response Evaluation Criteria in Solid 
Tumor (RECIST) version 1.1.
Objectives - Safety and Efficacy Expansion in Patients with Triple Negative Breast 
Cancer (TNBC)
Primary Objective
•
To evaluate the anti-tumor activity of PF-05212384 plus cisplatin in patients with 
TNBC.
Secondary Objectives
•
To continue to evaluate the overall safety profile of the combination of PF-05212384 
plus cisplatin.
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•
To characterize single and multiple dose pharmacokinetics following intravenous 
(IV) administration of PF-05212384.
•
To characterize the effects of the combinations on the potential to prolong the QTc 
interval.
•
To evaluate additional anti-tumor activity.
•
To assess patient reported outcomes (PRO) of global quality of life (QOL) and 
disease/treatment-related symptoms of advanced breast cancer.
 
 
Endpoints - Safety and Efficacy Expansion in patients with TNBC.
Primary Endpoint
•
Objective response (OR) as assessed by the Investigator using RECIST version 1.1.
Secondary Endpoints
•
Adverse Events as characterized by type, frequency, severity (as graded by NCI 
CTCAE v.4.03), timing, seriousness and relationship to study therapy.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
•
Single and multiple dose PK parameters of PF-05212384.
•
QTc interval.
•
Clinical Benefit Response (CBR), Duration of Response (DR) and Progression Free 
Survival (PFS) (as assessed using RECIST version 1.1).
•
Time to deterioration in global QOL.
•
Change from baseline in global QOL and disease/treatment-related symptoms.
 
 
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Study Design:
This is a Phase 1b, three-arm, open-label, multi-center, multiple dose, dose escalation, safety, 
tolerability, pharmacokinetic and pharmacodynamic study of PF-05212384 in combination 
with anti-tumor agents in sequential cohorts of adult patients with select advanced solid 
tumors.  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.  Based on the tolerability of 
PF-05212384 at higher doses in other (monotherapy) studies, the study will test increasing 
doses of PF-05212384 in combination with docetaxel, cisplatin, and/or dacomitinib in order 
to select the best dose to administer in the MTD expansion portion of the study.  
A modified toxicity probability interval (mTPI) method with adjustment based on observed 
DLT rate will be used to guide the dose assignment in Arms A and B.  The actual dose 
selected for the next cohort will take into account the recommended dose by using the 
adjusted mTPI method as well as safety data other than DLTs.  In Arm C in order to evaluate 
concurrent doses of dacomitinib in combination with two concurrent doses of PF-05212384, 
a zone-based design will be utilized, which is a modified 3+3 design that potentially allows 
opening of more than one dose level at the same time.35  In all arms, dose escalation will 
proceed until an MTD (or two MTDs) is declared, or the Maximum Allowable Dose is 
reached.
On April 1, 2015, Pfizer Inc. has decided to stop enrolment in Arms A and C of the 
B2151002 clinical trial.  Patients previously identified for enrolment in Arm A and C were 
permitted to enter the study after notification of the decision.  Due to closure, the MTD of 
those combinations will not be established.  All references to objectives, endpoints, study 
design, assessments, etc. and analysis of data in Arm A and C will be limited to the number 
of patients treated up to the enrolment discontinuation date for each Arm (June 10, 2015 for 
Arm A and 06 July 2015 for Arm C).  The decision is based on the company’s change in 
prioritization for the portfolio and is not due to any safety/efficacy concerns or regulatory 
interactions.
For Arm B, the study was originally designed as a dose escalation study with no expansion 
cohorts.  However, Protocol Amendment 5 includes the rationale and description for the 
safety and efficacy expansion with PF-05212384 plus cisplatin in patients with metastatic or 
locally-recurrent/advanced TNBC. A total of 21 patients were enrolled in Arm A, 33 in 
Arm B and 33 patients in Arm C.  Approximately 124 patients are expected overall including 
the safety and efficacy expansion. Pharmacodynamic studies will be performed in paired 
tumor biopsies, when clinically feasible, to evaluate PI3K and mTOR pathway inhibition at 
the PF-05212384 doses used in the MTD.  Paired biopsies that are obtained during dose 
escalation and expansion will also be evaluated for modulation of PI3K signaling.
Each of the treatment arms are restricted to patients with tumor types for which the 
combination partner is either considered standard-of-care, or in the case of dacomitinib, are 
indications which have been shown to be sensitive. 
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Figure 1.
Original Overall Study Design
CRPC: Castrate resistant prostate cancer; NSCLC: Non-small cell lung cancer; ABC: Advanced breast cancer; 
TCC: Transitional cell cancer; TNBC: Triple negative breast cancer; OC: ovarian cancer; HNSCC: Head and 
neck squamous cell cancer; BC: Breast cancer
Figure 2.
Amendment 5 Study Design
To understand the single-dose safety and single dose PK of the study drug, a lead in period 
will be included.  A single lead-in dose of PF-05212384 will be given either 7 days prior to 
Cycle 1 Day 1 (Arms A and B) or 14 days prior to Cycle 1 Day 1 (Arm C). The lead in 
period duration, subsequent doses, regimens and PK time-points may be modified based on 
the PK profile observed during the lead in period.  Patients will then receive study treatment 
on an outpatient basis as 21 day cycles.  
OC
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Treatment with study drug will continue until progression of disease, uncontrollable toxicity, 
a decision by the patient or Investigator to discontinue treatment, or the study is terminated.  
Patients experiencing toxicity may be managed with dose modification or discontinuation.  If 
a patient discontinues PF-05212384 or the combination partner (cisplatin, docetaxel or 
dacomitinib) due to toxicity which is specific to either agent, continuation of patient 
treatment within the study with single agent PF-05212384, cisplatin, docetaxel, or 
dacomitinib will be discussed with the Sponsor on a case-by-case basis. 
Statistical Method:
The MTD estimation in Arms A and B employs the mTPI method with adjustment of dose 
assignment criteria based on observed DLT rate. The mTPI method is a Bayesian method 
with only one assumption about the dose-toxicity relationship, which is, toxicity increases as 
dose increases.  For Arm C, a zone-based design will be employed for MTD estimation.  This 
is a 3+3 design modified for 2-dimensional MTD finding.  The expansion portion of the 
study with cisplatin in combination with PF-05212384 in patients with metastatic or 
locally-recurrent TNBC will assess safety and efficacy in 2 separate groups of 15 patients, 
for a total of at least 30 patients.
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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the ASSESSMENTS section of 
the protocol for detailed information on each assessment required for compliance with the protocol.  The Investigator may schedule 
visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct evaluations or assessments required 
to protect the well being of the patient.
Arms A and B (Original Protocol through Amendment 4)
Protocol Activity
Cycle 1
Cycle 2 and beyond
End of 
Treatment26
Follow 
Up27
Screen/ 
Baseline1
7 Days prior 
to C1D1
Day 1
Day 2
Day 8
Day 15
Day 1
Day 8
Day 15
Visit Window
±1 day
±1 day
±1 day
±2 days
±2 days
±2 days
+7 days
Informed consent2
X
Tumor history3
X
Medical history4
X
Baseline signs and symptoms5
X
Physical cxamination6
X
X
X
X
Abbreviated physical 
examination6
X
X
Weight
X
X
X
X
Vital signs7
X
X
X
X
X
X
Performance status8
X
X
X
X
X
Laboratory9 and other Safety Assessments
Hematology10
X
X
X
X
X
X
X (Cycle 2 
only)
X
Blood chemistry11
X
X
X
X
X
X
X (Cycle 2 
only)
X
Coagulation12
X
X
X
X
X
Urinalysis13
X
X
X
X
X
Pregnancy test14
X
X
X
X
ECG (12-lead)15
X
X
X (Cycle 
2 only)
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Protocol Activity
Cycle 1
Cycle 2 and beyond
End of 
Treatment26
Follow 
Up27
Screen/ 
Baseline1
7 Days prior 
to C1D1
Day 1
Day 2
Day 8
Day 15
Day 1
Day 8
Day 15
Visit Window
±1 day
±1 day
±1 day
±2 days
±2 days
±2 days
+7 days
Tumor Assessments
CT/MRI scan 17
X
X (every 6 
weeks)
X
Other Clinical Assessments
Adverse events (AE) 18
X
Continuous assessment and monitoring
X
X
Concomitant medications19
X
Continuous assessment and monitoring
X
X
Registration and Study Treatment20
Registration21
X
PF-05212384 IV20
Refer to Schedule of Study Treatment And Pharmacokinetic Assessments Table
Docetaxel IV (Arm A only) 20
Cisplatin IV (Arm B only)20
Pharmacokinetics and Pharmacodynamics
Pharmacokinetics22
Refer to Schedule of Study Treatment And Pharmacokinetic Assessments Table
Archival tumor biopsy for 
biomarker analysis23
X
Paired tumor biopsies for 
pharmacodynamic biomarkers24
X
X
X
Safety laboratory tests (hematology, blood chemistry, urinalysis, coagulation) and tumor assessments may be done up to 72 hours prior to scheduled 
Day 1 visit on any cycle to facilitate availability of results to Investigator at the time of clinic visit.  No time window is allowed for pregnancy test.
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Arm C only (Original Protocol through Amendment 4) 
Protocol Activity
Cycle 1
Cycle 2 and beyond
End of 
Treatment26 Follow 
Up27
Screen/ 
Baseline1
14 Days 
prior to 
C1D1
7 Days 
prior to 
C1D1
Day 1
Day 2
Day 8
Day 15
Day 1
Day 8
Day 15
Visit Window
±1 day
±1 day
±1 day
±1 day
±2 days ±2 days
±2 days
+7 days
Informed consent2
X
Tumor history3
X
Medical history4
X
Baseline signs and symptoms5
X
Physical examination6
X
X
X
X
Abbreviated physical
examination6
X
X
Weight
X
X
X
X
Vital signs7
X
X
X
X
X
X
X
Performance status8
X
X
X
X
X
Laboratory9 and other Safety Assessments
Hematology10
X
X
X
X
X
X
X (Cycle 2 
only)
X
Blood chemistry11
X
X
X
X
X
X
X (Cycle 2 
only)
X
Coagulation12
X
X
X
X
X
Urinalysis13
X
X
X
X
X
Pregnancy test14
X
X
X
X
ECG (12-lead) 15
X
X
X
X
LVEF16
X
X (every 3/6 
cycles)
Tumor Assessments
CT/MRI scan 17
X
X (every 6 
weeks)
X
Other Clinical Assessments
Adverse events (AE) 18
X
Continuous assessment and monitoring
X
X
Concomitant medications19
X
Continuous assessment and monitoring
X
X
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Protocol Activity
Cycle 1
Cycle 2 and beyond
End of 
Treatment26 Follow 
Up27
Screen/ 
Baseline1
14 Days 
prior to 
C1D1
7 Days 
prior to 
C1D1
Day 1
Day 2
Day 8
Day 15
Day 1
Day 8
Day 15
Visit Window
±1 day
±1 day
±1 day
±1 day
±2 days ±2 days
±2 days
+7 days
Registration and Study Treatment20
Registration21
X
PF-05212384 IV20
Refer to Schedule of Study Treatment And Pharmacokinetic Assessments Table
Dacomitinib PO (Arm C only) 20
Pharmacokinetics and Pharmacodynamics
Pharmacokinetics22
Refer to Schedule of Study Treatment And Pharmacokinetic Assessments Table
Archival tumor biopsy for 
biomarker analysis23
X
Paired tumor biopsies for 
pharmacodynamic biomarkers24
X
X
X
Safety laboratory tests (hematology, blood chemistry, urinalysis, coagulation) and tumor assessments may be done up to 72 hours prior to scheduled 
Day 1 visit on any cycle to facilitate availability of results to Investigator at the time of clinic visit.  No time window is allowed for pregnancy test.
Footnotes
1.
Screening/Baseline Assessments: must be completed within 28 days prior to study treatment start unless otherwise specified as shown in the schedule of 
events above.  Study treatment start is considered the lead-in dose; 7 days (Arms A and B) or 14 days (Arm C) prior to Cycle 1 Day 1.
2.
Informed Consent: must be obtained prior to undergoing any study specific procedures.
3.
Tumor History: will be collected within 28 days prior to first dose of study treatment.  History of oncology disease will be collected including details of 
primary diagnosis and treatment history (surgery, systemic treatment and radiotherapy) as well as duration and best response to immediate prior regimen if 
available.  When available, primary diagnosis history should include known molecular characteristics of the patient’s tumor including mutations, 
amplifications, etc. (eg, EGFR mutation, HER2 expression, etc).
4.
Medical History: will be collected within 28 days prior to first dose of study treatment.  Includes history of disease process other than oncology (active or 
resolved) and concomitant illnesses.  Includes prior treatment including dosing and duration of administration as well as verification of concurrent 
medication.
5.
Baseline Signs & Symptoms: patients will be asked about any signs and symptoms experienced within the past 14 days of study treatment start. During 
study treatment, any new or worsened conditions since baseline will be reported on the Adverse Event CRF.  
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6.
Physical Exam: will include an assessment for emergent toxicities or changes from prior visits.  These procedures may be conducted by the Investigator or 
his/her designee. Abbreviated physical exams should be performed where a complete physical exam is not required, and on an as needed basis for 
assessment of adverse events.  Abbreviated exams should be targeted to specific symptoms or complaints and be consistent with local standard of care. 
7.
Vital signs: will include height (baseline only), weight, blood pressure and heart rate to be recorded in the sitting position after approximately 5 minutes of 
rest.
8.
Performance status: per ECOG scale to be assessed within 14 days prior to the first dose of study treatment, and as described in the table above (see
Appendix 4).
9.
Laboratory Tests: will be performed as indicated within 14 days prior to the first dose of study treatment and during treatment as described in the table 
above.  Additional laboratory tests may be performed when medically indicated.
10. Hematology: to include platelet count, hemoglobin, and WBC count with 5- part differential.  No need to repeat on day of first dose of study treatment if 
baseline assessment performed within 7 days.
11. Blood Chemistry: to include AST (SGOT), ALT (SGPT), serum creatinine, total bilirubin, alkaline phosphatase, lactate dehydrogenase, chloride, uric acid, 
phosphorus, calcium, magnesium, potassium, sodium, BUN or urea, total protein, albumin, glucose (fasting), and insulin.  HbA1c at screen/baseline, and 
then every other cycle or as indicated in the event of suspected hyperglycemia. No need to repeat on day of first dose of study treatment if baseline 
assessment performed within 72 hours.  It is recommended that patients be under fasting conditions (no food or drink within 8 hours) for all blood chemistry 
panels on Day 1 of each cycle.  
12. Coagulation Tests: to include partial thromboplastin time (PTT) and international normalized ratio (INR). No need to repeat on day of first dose of study 
treatment if baseline assessment performed within 72 hours. 
13. Urinalysis: by dipstick is acceptable.  Microscopic analyses if dipstick deemed abnormal per Investigator discretion.  No need to repeat on day of first dose 
of study treatment if baseline assessment performed within 72 hours.
14. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed on two occasions prior to starting study therapy - once at the start of screening and once immediately before the lead-in dose.  Pregnancy tests 
will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and whenever one menstrual cycle is missed or 
when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required by local 
regulations.
15. ECG: Triplicate 12-lead ECG (per institutional practice) will be performed.  At each time point, three consecutive 12-lead ECGs will be performed 
approximately 2 minutes apart to determine mean QTc interval using Fredericia’s correction formula.  ECGs will be collected as follows: 
•
Within 14 days prior to the first dose of study treatment;
•
Cycle 1 Day 2, immediately prior to completion of PF-05212384 infusion;
•
Cycle 2 Day 1, immediately prior to completion of PF-05212384 infusion;
•
Subsequent cycles on Day 1, immediately prior to completion of PF-05212384 infusion (Arm C only);
•
End of Treatment Visit (Arm C only).
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The ECG should be collected prior to scheduled PK collections; the timing of the PK collections over rides the timing for ECG collections (ie, if a PK 
sample is scheduled at 1 hour post dose and an ECG is scheduled 1 hour post dose, then the ECGs should be collected just prior to the hour PK collection, 
and the PK sample should be collected at the nominal time).  If the patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, 
seizures, or stroke) an ECG should be obtained at time of the event.  See Section 7 for additional considerations regarding ECG.  If the mean QTc is 
prolonged (value of ≥500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation. Additional ECGs may be 
performed as clinically indicated.
16. Left ventricular ejection fraction (LVEF) ARM C:  LVEF will be measured at baseline, the end of Cycle 3, end of Cycle 6, and then every 6 cycles for 
Arm C patients only.  It will be measured by either echocardiogram (ECHO) or multi-gated radionucleide study (MUGA), with the same technique used 
throughout the study for an individual patient.  If an absolute decrease in LVEF of greater than 20% is noted by either MUGA or ECHO, then the LVEF will 
be repeated as soon as feasible using the alternate radiologic method (if available); if the decrease is verified further, interruption of treatment for futher 
cardiac evaluation will be undertaken per the judgment of Investigator.  In the absence of clinical signs and symptoms of left ventricular dysfunction or 
LVEF <40%, treatment may continue if judgment of the Investigator is that patient may benefit from ongoing therapy.  For any patient discontinuing therapy 
for signs or symptoms suggestive of left ventricular dysfunction, continued evaluation of LVEF at about 3-4 month interval to assess for resolution is 
recommended.
17. Tumor Assessments: Tumor assessments will be performed every 6 weeks (±5 days) while the patient is receiving treatment regardless of treatment delays. 
Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  A thoracic CT 
scan should be performed at every tumor assessment independent of lung involvement and in the absence of respiratory symptoms.  Brain scans and bone 
scans will be performed at baseline if disease is suspected and on-study as appropriate to follow disease. Baseline CNS imaging is not required with the 
exception of symptomatic patients to rule out CNS metastases. Given the exploratory nature of the study, confirmation of response (CR/PR) is not required 
but can be collected.  Tumor assessment should be repeated at the end of treatment visit if more than 6 weeks have passed since the last evaluation.  For 
those patients who discontinue for reasons other than progression of disease, tumor assessments should continue until progression of disease is documented. 
In patients continuing on study for >12 cycles and have experienced manageable toxicity and stable disease, the interval between imaging assessments may 
be modified from every 6 weeks (±5 days) to every 9 weeks (±5 days) if the Investigator determines it is in the best interest of the patient, and after 
discussion and approval by the Sponsor.  The modification will decrease the burden on the patients and sites, while still ensuring adequate monitoring for 
safety and efficacy. 
18. Adverse Event (AE) Assessments: AEs should be documented and recorded at each visit using NCI CTC AE version 4.03 (Appendix 3).  Patients must be 
followed for AEs for 28 days after the last treatment administration or until all drug related toxicities have resolved, whichever is later; or earlier than 
28 days should the patient commence another anticancer therapy within that time frame.  For SAEs, the active reporting period to Pfizer or its designated 
representative begins from the time that the patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to 
undergoing any study-related procedure and/or receiving investigational product, through and including 28 calendar days after the last administration of the 
investigational product.  SAEs occurring after the active reporting period has ended should be reported to the Sponsor if the Investigator becomes aware of 
them; at a minimum, all SAEs that the Investigator believes have at least a reasonable possibility of being related to study drug are to be reported to the 
Sponsor.
19. Concomitant Medications: All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and 
prophylaxis), and the drugs used to treat adverse events or chronic diseases.
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20. Study Treatment: Patients will be treated with PF-05212384 once weekly in 3 week cycles.  Docetaxel and Cisplatin will be given once every 3 weeks.  
Dacomitinib will be taken daily. Details on study treatment are provided in the Schedule of STUDY TREATMENTS and Pharmacokinetics Assessments.  
21. Registration: Patient enrollment number, treatment arm, and dose level allocation assigned by Pfizer Inc.
22. PK Sampling: Details on sampling are provided in the Schedule of STUDY TREATMENTS and Pharmacokinetics Assessments.  
23. Archival tumor biopsy for biomarker analysis: All patients will be required to provide an archived tumor biopsy formalin fixed paraffin embedded
(FFPE) sample.  If an archived tumor sample is not available, patients must consent to provide a fresh biopsy FFPE for purpose of this analysis.  Patients 
may not be enrolled into the study without providing either an archived or fresh tumor sample.  For the tumor biopsy sample, paraffin blocks are preferred, 
but freshly cut slides are acceptable.  Details for handling of these samples including processing, storage, and shipment will be provided in the Study 
Manual.  Collection of archival tissue post announcement of Pfizer’s decision to close Arm A and C is at the discretion of the investigator (in the event 
archival tissue is not available, a fresh biopsy is no longer required).  The requirement for collection of archival tissue for patients enrolling in Arm B 
remains unchanged.
24. Paired tumor biopsies for pharmacodynamic (PD) biomarkers (see Section 7.3): Fresh FFPE tumor biopsies will be requested at Screening (within 
28 days of study treatment start) and on Cycle 2 Day 8 for all patients in both the dose escalation and the MTD cohorts in order to demonstrate pathway 
inhibition and for PD biomarker studies across doses.  The paired tumor biopsy will be mandatory for patients enrolled in the MTD cohort unless it poses a 
safety risk to the patient in the opinion of the Investigator after discussion with the Sponsor. Tumor biopsies collected at End of Treatment are optional, but 
are highly desired, for a proteomics-based evaluation of possible resistance mechanisms to PI3K/Akt/mTOR axis therapies.  Details for handling of these 
samples including processing, storage, and shipment will be provided in the Study Manual.  
 
 
26. End of treatment visit: Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments).
27. Follow up: At least 28 days, and no more than 35 days after discontinuation of treatment patients will return to undergo review of concomitant medications, 
vital signs, and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity at this point following discontinuation 
of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the Investigator, that no further 
improvement is expected.  For those patients who discontinue for reasons other than progression of disease, tumor assessments should continue until 
progression of disease is documented.
&&,
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SCHEDULE OF STUDY TREATMENT AND PHARMACOKINETIC ASSESSMENTS ARM A (Original Protocol through 
Amendment 4)
Cycle 1
Cycle 2
Cycle 3 - 6
Cycle 7 and Beyond
Protocol Activity
Screen/ 
Baseline
7 days 
prior to 
C1D1
Day 
1
Day 
2
Day
8
Day
15
Day 
1
Day
8
Day
15
Day 
1
Day
8
Day
15
Day
1
Day
8
Day
15
Study Treatment1
PF-05212384
X
X
X
X
X
X
X
X
X
X
X
X
X
Docetaxel
X
X
X
X
Pharmacokinetics
PK for PF-052123842
X
X
X
PK for Docetaxel3
X
X
1.
Study Treatment: Arm A treatment with PF-05212384 will be initiated 7 days prior to Cycle 1 Day 1.  On Cycle 1 Day 1 patients will receive docetaxel 
alone.  On Cycle 1 Day 2, patients will receive treatment with PF-05212384 alone.  On Day 1 for Cycles 2 and beyond, patients will receive docetaxel 
followed by PF-05212384.  
2.
PK Sampling for PF-05212384: Blood samples for pharmacokinetics will be taken at 0 hours (pre-dose), 0.5 hours (immediately after the infusion of 
PF-05212384), 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose 7 days prior to Cycle 1 Day 1 and on Cycle 2 Day 1.  Pre-dose samples will be collected on 
Day 1 for Cycles 3-6.
3.
PK Sampling for Docetaxel: Blood samples for pharmacokinetics will be taken at 0 hours (pre-dose), 1 hour (immediately after the infusion of Docetaxel) 
1.5, 2, 4, 6, and 24 hours post-dose on Day 1 for Cycles 1 and 2.
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SCHEDULE OF STUDY TREATMENT AND PHARMACOKINETIC ASSESSMENTS ARM B (Original Protocol through 
Amendment 4)
Cycle 1
Cycle 2
Cycle 3 - 6
Cycle 7 and Beyond
Protocol Activity
Screen/ 
Baseline
7 days 
prior to 
C1D1
Day 
1
Day 
2
Day 
8
Day
15
Day 
1
Day 
8
Day
15
Day 
1
Day 
8
Day
15
Day
1
Day
8
Day
15
Study Treatment1
PF-05212384
X 
X
X
X
X
X
X
X
X
X
X
X
X
Cisplatin
X
X
X
X
Pharmacokinetics
PK for PF-052123842
X 
X
X
PK for Cisplatin3
X
X
1.
Study Treatment: Arm B treatment with PF-05212384 will be initiated 7 days prior to Cycle 1 Day 1.  On Cycle 1 Day 1 patients will receive cisplatin 
alone.  On Cycle 1 Day 2,  patients will receive treatment with PF-05212384 alone.  On Day 1 for Cycles 2 and beyond, patients will receive cisplatin 
followed by PF-05212384.  
2.
PK Sampling for PF-05212384: Blood samples for pharmacokinetics will be taken at 0 hours (pre-dose), 0.5 hours (immediately after the infusion of 
PF-05212384), 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose 7 days prior to Cycle 1 Day 1 and on Cycle 2 Day 1.  Pre-dose samples will be collected on 
Day 1 for Cycles 3-6. 
3.
PK Sampling for Cisplatin: Blood samples for pharmacokinetics will be taken at 0 hours (pre-dose), 2 hour (immediately after the infusion of Cisplatin) 
2.5, 3, 4, 6, and 24 hours post-dose on Day 1 for Cycles 1 and 2.
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SCHEDULE OF STUDY TREATMENT AND PHARMACOKINETIC ASSESSMENTS ARM C (Original Protocol through 
Amendment 4)
Cycle 1
Cycle 2
Cycle 3 - 6
Cycle 7 and 
Beyond
Protocol Activity
Screen/ 
Baseline
14 Days 
prior to 
C1D1
7 Days 
Prior to 
C1D1
Day
1
Day
2
Day
8
Day
15
Day
1
Day
8
Day
15
Day
1
Day
8
Day
15
Day
1
Day
8
Day
15
Study Treatment1 
PF-05212384
X
X
X
X
X
X
X
X
X
X
X
X
X
Dacomitinib
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics
PK for PF-052123842
X
X
X
PK for Dacomitinib5
X
X
1.
Study Treatment: Arm C: treatment with PF-05212384 will be initiated 14 days prior to Cycle 1 Day 1. 7 days prior to Cycle 1 Day 1 the patient will 
initiate dacomitinib which will be taken orally daily.  On Cycle 1 Day 1 patients will receive dacomitinib only.  On Cycle 1 Day 2, patients will receive 
treatment with dacomitinib followed by PF-05212384.  On Day 1 for Cycles 2 and beyond, patients will receive dacomitinib followed by PF-05212384.  
2.
PK Sampling for PF-05212384: Blood samples for pharmacokinetics will be taken at 0 hours (pre-dose), 0.5 hours (immediately after the infusion of 
PF-05212384), 1, 2, 4, 6, 24, 72, 96 and 168 hours post-dose 14 days prior to Cycle 1 Day 1 and on Cycle 2 Day 1.  Pre-dose samples will be collected on 
Day 1 for Cycles 3-6. 
3.
PK Sampling for Dacomitinib: Blood samples for pharmacokinetics will be taken at 0 hours (pre-dose), 1, 2, 4, 6, and 24 hours post-dose on Day 1 for 
Cycles 1 and 2.
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Schedule of Activities for Safety and Efficacy Expansion with PF-05212384 plus Cisplatin in Patients with TNBC
Cycle 1
Cycle 2 and Beyond
End of 
Treatment29
Follow 
Up30
Screen/ 
Baseline1
Day 1
Day 2
Day 8
Day 15
Day 1
Day 8
Day 15
Visit Window
±1 day
±1 day
±2 days
±2 days
±2 days
+7 days
Informed consent2
X
Tumor history3
X
Medical history4
X
Baseline signs and 
symptoms5
X
Physical cxamination6
X
X
X
Abbreviated physical 
examination6
X
X
Weight
X
X
X
X
Vital signs7
X
X
X
X
X
Performance status8
X
X
X
X
Laboratory9 and other 
Safety Assessments
Hematology10
X
X
X
X
X
X
(Cycle 2 only)
X
Blood chemistry11
X
X
X
X
X
X
(Cycle 2 only)
X
Coagulation12
X
X
X
X
Urinalysis13
X
X
X
X
Pregnancy test14
X
X
X
ECG (12-lead)15
X
X
X
X
Tumor Assessments
CT/MRI scan16
X
X
(every 6 wks)
X
Other Clinical Assessments
Adverse events (AE)17
X
→
→
→
→
→
→
→
→
X
Concomitant medications18
X
→
→
→
→
→
→
→
→
X
EORTC QLQ-C30, EORTC 
QLQ BR-2319
X
X
X
X
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Cycle 1
Cycle 2 and Beyond
End of 
Treatment29
Follow 
Up30
Screen/ 
Baseline1
Day 1
Day 2
Day 8
Day 15
Day 1
Day 8
Day 15
Visit Window
±1 day
±1 day
±2 days
±2 days
±2 days
+7 days
Registration and Study 
Treatment20
Registration21
X
Pharmacokinetics and 
Pharmacodynamics22
Mandatory archival FFPE 
tumor tissue23
X
Safety laboratory tests (hematology, blood chemistry, urinalysis, coagulation) and tumor assessments may be done up to 72 hours prior to scheduled 
Day 1 visit on any cycle to facilitate availability of results to Investigator at the time of clinic visit.  No time window is allowed for pregnancy test.
Footnotes
1.
Screening/Baseline Assessments: must be completed within 28 days prior to study treatment start unless otherwise specified as shown in the schedule of 
events above.  
2.
Informed Consent: must be obtained prior to undergoing any study specific procedures.
3.
Tumor History: will be collected within 28 days prior to first dose of study treatment.  History will include details of treatment history (surgery, systemic 
treatment and radiotherapy) as well as duration and best response to immediate prior regimen if available.  When available, history should include known 
molecular characteristics of the patient’s tumor including mutations, amplifications, etc. (eg, PI3K, PTEN, HER family, AR, etc).
&&,
&&,
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4.
Medical History: will be collected within 28 days prior to first dose of study treatment.  Includes history of disease process other than oncology (active or 
resolved) and concomitant illnesses.  Includes prior treatment including dosing and duration of administration as well as verification of concurrent 
medication.
5.
Baseline Signs & Symptoms: patients will be asked about any signs and symptoms experienced within the past 14 days of study treatment start.  During 
study treatment, any new or worsened conditions since baseline will be reported on the Adverse Event CRF.  
6.
Physical Exam (PE): performed at Screen/Baseline.  EOT and F/U PE will include an assessment for emergent toxicities or changes from prior visits.  
These procedures may be conducted by the Investigator or his/her designee.  Abbreviated physical exams should be performed where a complete physical 
exam is not required, and on an as needed basis for assessment of adverse events.  Abbreviated exams should be targeted to specific symptoms or complaints 
and be consistent with local standard of care. 
7.
Vital signs: will include height (baseline only), weight, blood pressure and heart rate to be recorded in the sitting position after approximately 5 minutes of 
rest.
8.
Performance status: per ECOG scale to be assessed within 14 days prior to the first dose of study treatment, and as described in the table above (see 
Appendix 4).
9.
Laboratory Tests: will be performed as indicated within 14 days prior to the first dose of study treatment and during treatment (pre-dose) as described in 
the table above.  Additional laboratory tests may be performed when medically indicated.
10. Hematology: to include platelet count, hemoglobin, and WBC count with 5-part differential.  No need to repeat on day of first dose of study treatment if 
baseline assessment performed within 7 days.
11. Blood Chemistry: to include AST (SGOT), ALT (SGPT), serum creatinine, total bilirubin, alkaline phosphatase, lactate dehydrogenase, chloride, uric acid, 
phosphorus, calcium, magnesium, potassium, sodium, BUN or urea, total protein, albumin, glucose (fasting), and insulin.  HbA1c at screen/baseline, and 
then every other cycle or as indicated in the event of suspected hyperglycemia. No need to repeat on day of first dose of study treatment if baseline 
assessment performed within 72 hours.  It is recommended that patients be under fasting conditions (no food or drink within 8 hours) for all blood chemistry 
panels on Day 1 of each cycle.  
12. Coagulation Tests: to include partial thromboplastin time (PTT), or abbreviated partial thromboplastin time (aPTT) if PTT not routinely performed, and 
international normalized ratio (INR). No need to repeat on day of first dose of study treatment if baseline assessment performed within 72 hours.
13. Urinalysis: by dipstick is acceptable.  Microscopic analyses if dipstick deemed abnormal per Investigator discretion.  No need to repeat on day of first dose 
of study treatment if baseline assessment performed within 72 hours.
14. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed on two occasions prior to starting study therapy - once at the start of screening and once again at least 72 hours prior to Cycle 1 Day 1.  Pregnancy 
tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and whenever one menstrual cycle is missed 
or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required by local 
regulations.
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15. ECG: Triplicate 12-lead ECG (per institutional practice) will be performed.  At each time point, three consecutive 12-lead ECGs will be performed 
approximately 2 minutes apart to determine mean QTc interval using Fredericia’s correction formula.  ECGs will be collected as follows: 
•
Within 14 days prior to the first dose of study treatment;
•
Day 1 of all Cycles: pre-PF-05212384 infusion and immediately prior to completion of PF-05212384 infusion;
•
End of Treatment Visit.
The ECG should be collected prior to scheduled PK collections; the timing of the PK collections over rides the timing for ECG collections (ie, if a PK 
sample is scheduled at 1 hour post dose and an ECG is scheduled 1 hour post dose, then the ECGs should be collected just prior to the hour PK collection, 
and the PK sample should be collected at the nominal time).  If the patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke) an ECG should be obtained at time of the event.  See Section 7 for additional considerations regarding ECG.  If the mean QTc is prolonged (value 
of ≥500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation. Additional ECGs may be performed as clinically 
indicated.
16. Tumor Assessments: Tumor assessments will be performed every 6 weeks (±5 days) while the patient is receiving treatment regardless of treatment delays.   
Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen and pelvis CT or MRI scans.  A thoracic CT 
scan should be performed at every tumor assessment independent of lung involvement and in the absence of respiratory symptoms.  Brain scans and bone 
scans will be performed at baseline if disease is suspected and on-study as appropriate to follow disease. Baseline CNS imaging is not required with the 
exception of symptomatic patients to rule out CNS metastases. Confirmation of response (CR/PR) (at least) four weeks after initial response assessment is 
required. Tumor assessment should be repeated at the end of treatment visit if more than 6 weeks have passed since the last evaluation.  For those patients 
who discontinue for reasons other than progression of disease, tumor assessments should continue until progression of disease is documented. In patients 
continuing on study for >12 cycles and have experienced manageable toxicity and stable disease, the interval between imaging assessments may be modified 
from every 6 weeks (±5 days) to every 9 weeks (±5 days) if the Investigator determines it is in the best interest of the patient, and after discussion and 
approval by the Sponsor.  The modification will decrease the burden on the patients and sites, while still ensuring adequate monitoring for safety and 
efficacy. 
17. Adverse Event (AE) Assessments: AEs should be documented and recorded at each visit using NCI CTC AE version 4.03 (Appendix 3).  Patients must be 
followed for AEs for 28 days after the last treatment administration or until all drug related toxicities have resolved, whichever is later; or earlier than 
28 days should the patient commence another anticancer therapy within that time frame.  For SAEs, the active reporting period to Pfizer or its designated 
representative begins from the time that the patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to 
undergoing any study-related procedure and/or receiving investigational product, through and including 28 calendar days after the last administration of the 
investigational product.  SAEs occurring after the active reporting period has ended should be reported to the Sponsor if the Investigator becomes aware of 
them; at a minimum, all SAEs that the Investigator believes have at least a reasonable possibility of being related to study drug are to be reported to the 
Sponsor.
18. Concomitant Medications: All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and 
prophylaxis), and the drugs used to treat adverse events or chronic diseases.
19. EORTC QLQ-C30 and QLQ-BR23: Patients must complete all QLQ-C30 and QLQ-BR-23 self-assessment questionnaires in the clinic at the specified 
time points prior to any other study or medical procedures and prior to any discussion of their progress with the physician or clinic personnel. The 
questionnaires cannot be taken home. After Cycle 2, all assessments occur on Day 1 of each cycle.
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20. Study Treatment: Patients will be treated with PF-05212384 once weekly in 3 week cycles.  Cisplatin will be given once every 3 weeks. Details on study 
treatment are provided in the Schedule of STUDY TREATMENTS and Pharmacokinetics Assessments.   
21. Registration: Patient enrollment number assigned by Pfizer Inc. (or designee). 
22. PK Sampling: Details on sampling are provided in the Schedule of STUDY TREATMENTS and Pharmacokinetics Assessments.
23. Archival tumor biopsy for biomarker analysis: All patients will be required to provide an archived tumor biopsy formalin fixed paraffin embedded
(FFPE) sample.  If an archived tumor sample is not available, patients must consent to provide a fresh biopsy FFPE for purpose of this analysis.  Patients 
may not be enrolled into the study without providing either an archived or fresh tumor sample.  For the tumor biopsy sample, paraffin blocks are preferred, 
but freshly cut slides are acceptable.  Details for handling of these samples including processing, storage, and shipment will be provided in the Study 
Manual.  
 
 
 
 
 
 
 
29. End of treatment visit: Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments).
30. Follow up: At least 28 days, and no more than 35 days after discontinuation of treatment patients will return to undergo review of concomitant medications, 
vital signs, and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity at this point following discontinuation 
of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the Investigator, that no further 
improvement is expected.  For those patients who discontinue for reasons other than progression of disease, tumor assessments should continue until 
progression of disease is documented.
&&,
&&,
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SCHEDULE OF STUDY TREATMENT AND PHARMACOKINETIC ASSESSMENTS – PF-05212384 plus Cisplatin in 
Patients with TNBC
Cycle 1
Cycle 2
Cycle 3 - 6
Cycle 7 and Beyond
Protocol Activity
Day 
1
Day 
2
Day 
8
Day
15
Day 
1
Day 
2
Day 
8
Day
15
Day 
1
Day 
8
Day
15
Day
1
Day
8
Day
15
Study Treatment1
PF-05212384
X
X
X
X
X
X
X
X
X
X
X
X
Cisplatin
X
X
X
X
Pharmacokinetics
PK for PF-052123842
X
X
X
X
X
X
X
1.
Study Treatment: On Cycle 1 Day 1 patients will receive cisplatin followed by PF-05212384 approximately 30 minutes after completion of cisplatin 
infusion.  
2.
PK Sampling for PF-05212384: Cycle 1 Day 1 and Cycle 2 Day 1:  Blood samples for pharmacokinetics will be taken at 0 hours (pre-dose), 0.5 hours 
(immediately after the infusion of PF-05212384), 1, 2, 4, 6, 24, 72, and 168 (predose Day 8) hours post-dose.  Pre-dose samples will be collected on Day 1 
for Cycles 3-6. 
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................34
LIST OF FIGURES .................................................................................................................34
APPENDICES .........................................................................................................................35
1. INTRODUCTION ...............................................................................................................36
1.1. Indication – Original Protocol through Amendment 4............................................36
1.2. Indication – Amendment 5......................................................................................36
1.3. Background .............................................................................................................36
1.3.1. PI3K/mTOR................................................................................................36
1.3.2. PF-05212384...............................................................................................38
1.3.2.1. Preclinical Data for PF-05212384.............................................38
1.3.3. PF-05212384 Clinical Experience..............................................................39
1.3.3.1. Phase 1 Study of PF-05212384 Single Agent in Patients 
with Advanced Solid Tumors (B2151001)........................................39
1.3.3.2. Phase 1 Study of PF-05212384 in Combination with 
Irinotecan in Patients with Advanced Solid Tumors 
(B1271002)........................................................................................41
1.3.3.3. Phase 2 Study of PF-05212384 Single Agent in Patients 
with Advanced Endometrial Cancer (B1271004) .............................41
1.3.4. Docetaxel ....................................................................................................42
1.3.5. Cisplatin......................................................................................................42
1.3.5.1. PF-05212384 Plus Cisplatin in Patients with TNBC ................43
1.3.6. Dacomitinib (PF-00299804).......................................................................43
1.3.7. Study Rationale...........................................................................................46
1.3.7.1. Rationale for Combinations ......................................................47
1.3.7.2. Rationale for PF-05212384 Doses ............................................49
1.3.7.3. Rationale for Docetaxel, Cisplatin and Dacomitinib 
Starting Doses....................................................................................49
1.4. Overall Risk Benefit Assessment............................................................................49
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................50
2.1. Objectives – Original Protocol through Amendment 4...........................................50
2.2. Endpoints – Original Protocol through Amendment 4............................................50
2.3. Objectives - Safety and Efficacy Expansion in Patients with TNBC .....................51
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2.4. Endpoints - Safety and Efficacy Expansion in Patients with TNBC ......................51
3. STUDY DESIGN.................................................................................................................52
3.1. Dose Levels to Be Tested........................................................................................54
3.1.1. Criteria for Dose Assignment.....................................................................56
3.1.1.1. Criteria for Dose Assignments for Arms A and B ....................56
3.1.1.2. Criteria for Dose Assignment for Arm C..................................58
3.2. DLT Definition (All Arms).....................................................................................59
3.3. MTD Definition.......................................................................................................60
3.4. Safety and Efficacy Expansion in Patients with TNBC..........................................60
3.4.1. Dose Rationale............................................................................................61
4. PATIENT SELECTION......................................................................................................61
4.1. Inclusion Criteria – Original Protocol through Amendment 4................................62
4.2. Exclusion Criteria – Original Protocol through Amendment 4...............................64
4.3. Inclusion Criteria – Safety and Efficacy Expansion in patients with TNBC..........66
4.4. Exclusion Criteria – Safety and Efficacy Expansion in patients with TNBC.........68
4.5. Life Style Guidelines...............................................................................................70
4.6. Sponsor Qualified Medical Personnel.....................................................................71
5. STUDY TREATMENTS.....................................................................................................71
5.1. Allocation to Treatment ..........................................................................................71
5.1.1. Dose Escalation Portion of B2151002........................................................71
5.1.2. Safety and Efficacy Expansion in Patients with TNBC .............................72
5.2. Drug Supplies..........................................................................................................72
5.2.1. Formulation and Packaging........................................................................73
5.2.1.1. PF-05212384.............................................................................73
5.2.1.2. Docetaxel...................................................................................73
5.2.1.3. Cisplatin ....................................................................................73
5.2.1.4. Dacomitinib...............................................................................73
5.2.2. Preparation and Dispensing........................................................................73
5.2.2.1. PF-05212384.............................................................................73
5.2.2.2. Docetaxel...................................................................................74
5.2.2.3. Cisplatin ....................................................................................74
5.2.2.4. Dacomitinib...............................................................................74
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5.2.3. Administration............................................................................................74
5.2.3.1. PF-05212384.............................................................................74
5.2.3.2. Docetaxel...................................................................................75
5.2.3.3. Cisplatin ....................................................................................75
5.2.3.4. Dacomitinib...............................................................................76
5.2.4. Medication Errors .......................................................................................76
5.2.5. Recommended Dose Modifications............................................................77
5.2.6. Dose Interruptions/Delay............................................................................77
5.2.7. Dose Reductions.........................................................................................78
5.2.7.1. PF-05212384.............................................................................79
5.2.7.2. Docetaxel...................................................................................81
5.2.7.3. Cisplatin ....................................................................................82
5.2.7.4. Dacomitinib...............................................................................83
5.2.8. Compliance.................................................................................................84
5.2.8.1. PF-05212384, Docetaxel, and Cisplatin....................................84
5.2.8.2. Dacomitinib...............................................................................84
5.3. Drug Storage and Drug Accountability...................................................................85
5.3.1. PF-05212384...............................................................................................85
5.3.2. Docetaxel and Cisplatin..............................................................................86
5.3.3. Dacomitinib ................................................................................................86
5.4. Concomitant Medication(s).....................................................................................86
5.4.1. Drugs Interacting with CYP3A4 ................................................................86
5.4.2. CYP2D6 Substrates (Arm C only) .............................................................87
5.4.3. P-glycoprotein Substrates (Arm C only) ....................................................88
5.4.4. Strong Amines (Arm C only) .....................................................................88
5.4.5. Other Anti-tumor/Anti-cancer or Experimental Drugs...............................88
5.4.6. Supportive Care ..........................................................................................88
5.4.7. Hematopoietic Growth Factors...................................................................88
5.4.8. Corticosteroids............................................................................................89
5.4.9. Surgery........................................................................................................89
5.4.10. Oral Mucositis – Prophylaxis and Management.......................................89
6. STUDY PROCEDURES .....................................................................................................90
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6.1. Screening.................................................................................................................90
6.2. Study Period ............................................................................................................91
6.3. Follow-up Visit .......................................................................................................91
6.4. Patient Withdrawal..................................................................................................91
7. ASSESSMENTS..................................................................................................................93
7.1. Safety Assessments .................................................................................................93
7.1.1. Pregnancy Testing ......................................................................................93
7.1.2. Adverse Events...........................................................................................93
7.1.3. Laboratory Safety Assessments..................................................................94
7.1.4. Vital Signs and Physical Examination........................................................94
7.1.5. (12-Lead) ECG ...........................................................................................94
7.1.6. Left Ventricular Ejection Fraction Measurements (Arm C only)...............95
7.2. Pharmacokinetics Assessments...............................................................................96
7.2.1. Pharmacokinetic Assessments in the Safety and Efficacy Expansion 
in TNBC...........................................................................................................96
7.3. Pharmacodynamic Assessments..............................................................................97
7.3.1. Tumor Biopsy.............................................................................................98
7.3.2. Whole Blood/Plasma Biospecimens...........................................................99
7.3.3. Effect of PI3K Inhibition on Glucose Metabolism.....................................99
7.4. Tumor Response Assessments ................................................................................99
100
100
101
7.6. Patient Reported Outcomes in the Safety and Efficacy Expansion in TNBC.......101
7.6.1. EORTC QLQ-C30 and EORTC QLQ-BR23 ...........................................102
8. ADVERSE EVENT REPORTING....................................................................................102
8.1. Adverse Events......................................................................................................102
8.2. Reporting Period ...................................................................................................103
8.3. Definition of an Adverse Event.............................................................................103
8.4. Abnormal Test Findings........................................................................................104
8.5. Serious Adverse Events.........................................................................................104
8.5.1. Protocol-Specified Serious Adverse Events.............................................105
&&,
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8.5.2. Potential Cases of Drug-Induced Liver Injury..........................................105
8.6. Hospitalization ......................................................................................................107
8.7. Severity Assessment..............................................................................................108
8.8. Causality Assessment............................................................................................108
8.9. Exposure During Pregnancy..................................................................................109
8.10. Occupational Exposure .......................................................................................110
8.11. Withdrawal Due to Adverse Events (See also Section Patient Withdrawal) ......110
8.12. Eliciting Adverse Event Information ..................................................................110
8.13. Reporting Requirements......................................................................................110
8.13.1. Serious Adverse Event Reporting Requirements ...................................110
8.13.2. Non-Serious Adverse Event Reporting Requirements ...........................111
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............111
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................111
9.1. Analysis Sets .........................................................................................................111
9.2. Statistical Methods and Properties ........................................................................113
9.2.1. Statistical Methods for Arms A and B......................................................113
9.2.2. Statistical Method for Arm C ...................................................................114
9.2.3. Statistical Method for the Safety and Efficacy Expansion Arm 1 and 
2......................................................................................................................114
9.3. Sample Size Determination...................................................................................114
9.4. Efficacy Analysis ..................................................................................................115
9.4.1. Efficacy Analysis for the Dose Escalation ...............................................115
9.4.2. Efficacy Analysis for the Safety and Efficacy Expansion in TNBC........116
9.5. Analysis of Other Endpoints .................................................................................116
9.5.1. Analysis of Single- and Multiple-Dose Pharmacokinetics.......................116
9.5.1.1. Metabolite Profiling ................................................................117
9.5.2. Statistical Analysis of Biomarkers............................................................117
9.6. Safety Analysis......................................................................................................117
9.6.1. Analysis of Primary Endpoint ..................................................................117
9.6.2. Analysis of Secondary Safety Endpoints..................................................117
9.6.2.1. Adverse Events........................................................................117
9.6.2.2. Laboratory Tests Abnormalities..............................................118
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9.6.2.3. Electrocardiogram Assessments..............................................118
9.7. Patient Reported Outcomes...................................................................................118
9.8. Data Safety Monitoring Committee ......................................................................119
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................119
11. DATA HANDLING AND RECORD KEEPING ...........................................................119
11.1. Case Report Forms/Electronic Data Records......................................................119
11.2. Record Retention.................................................................................................120
12. ETHICS............................................................................................................................120
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..........120
12.2. Ethical Conduct of the Study ..............................................................................121
12.3. Patient Information and Consent.........................................................................121
12.4. Patient Recruitment.............................................................................................121
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................122
13. DEFINITION OF END OF TRIAL.................................................................................122
13.1. End of Trial in a Member State...........................................................................122
13.2. End of Trial in all other Participating Countries.................................................122
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................122
15. PUBLICATION OF STUDY RESULTS........................................................................122
15.1. Communication of Results by Pfizer ..................................................................122
15.2. Publications by Investigators ..............................................................................123
16. REFERENCES ................................................................................................................125
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LIST OF TABLES
Table 1.
Tumor Growth Inhibition with Single Agent PF-05212384.................................38
Table 2.
Phase 1 Study B2151001: Dose Limiting Toxicities by Preferred Term and 
Dose......................................................................................................................39
Table 3.
Phase 1 Study B2151001: Treatment-Related, Treatment Emergent 
Adverse Events by MedRA Preferred Term in ≥2 Patients; PF 05212384 
154 mg Dose Level (MTD) – All CTCAE Grades...............................................40
Table 4.
Phase 1 Study B2151001: Summary of Treatment-Related, 
Treatment-Emergent Adverse Events by MedRA Preferred Term; 
Maximum CTCAE Grades 3, 4, and 5 .................................................................40
Table 5.
Summary of Treatment-Related Adverse Events in ≥10% of Patients 
Treated with Single-Agent Dacomitinib...............................................................45
Table 6.
Summary of Treatment Related Adverse Events in ≥10% of Patients with 
NSCLC Treated with Dacomitinib at a Dose of 45 mg QD.................................46
Table 7.
Dose Levels for Arms A, B and C........................................................................55
Table 8.
Dose Escalation Sequence (Arm C) .....................................................................58
Table 9.
Possible Dose Levels of PF-05212384.................................................................79
Table 10.
PF-05212384 - Dose Modification Guidelines for Related Toxicities.................80
Table 11.
Docetaxel - Dose Modification Guidelines for Related Toxicities for a New 
Cycle Based on Worst Toxicity Observed in the Prior Cycle ..............................82
Table 12.
Cisplatin - Dose Modification Guidelines for Related Toxicities for a New 
Cycle Based on Worst Toxicity Observed in Prior Cycle ....................................83
Table 13.
Possible Dose Levels for Dacomitinib .................................................................84
Table 14.
Dacomitinib - Dose Modifications Guidelines for Related Toxicities Based 
on Worst Toxicity Observed.................................................................................84
Table 15.
List of Laboratory Test Assessments....................................................................94
Table 16.
Pharmacodynamic and Molecular Analysis Samples...........................................97
Table 17.
Probability of Escalating Dose Level .................................................................114
LIST OF FIGURES
Figure 1.
Original Overall Study Design .............................................................................10
Figure 2.
Amendment 5 Study Design.................................................................................10
Figure 3.
PI3K/mTOR and EGFR Signaling Pathways.......................................................37
Figure 4.
Tumor Growth Inhibition of PF-05212384 in Combination with Docetaxel 
Versus either compound alone in H1975 Lung Xenograft Model .......................47
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Figure 5.
Tumor Growth Inhibition of PF-05212384 in Combination with HKI-272 
(irreversible Her2 inhibitor) in H1975 Lung Xenograft Model............................48
Figure 6.
Original Overall Study Design .............................................................................53
Figure 7.
Recommended Action Based on Cumulative DLT Data at the Current Dose 
Level (Arms A and B) ..........................................................................................57
Figure 8.
Amendment 5 Study Design.................................................................................61
APPENDICES
Appendix 1. Abbreviations....................................................................................................130
Appendix 2. RECIST (Response Evaluation Criteria In Solid Tumors) Version 1.1 
Guidelines...........................................................................................................134
Appendix 3. National Cancer Institute (NCI) common Terminology Criteria for 
Adverse Events (CTCAE) ..................................................................................139
Appendix 4. Eastern Cooperative Oncology Group Performance Status..............................140
Appendix 5. Guidelines for Management of Hyperglycemia with PF-05212384.................141
Appendix 6. Skin Toxicity Management with PF-05212384................................................142
Appendix 7. Dacomitinib Adverse Event Management Guidelines......................................146
Appendix 8. CYP2D6 Substrates...........................................................................................154
Appendix 9. Management of Allergic Reactions or Anaphylaxis .........................................156
158
Appendix 11. BR23 English ..................................................................................................160
&&,
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1. INTRODUCTION
1.1. Indication – Original Protocol through Amendment 4
PF-05212384 in combination with other anti-tumor agents (docetaxel, cisplatin, and 
dacomitinib) is a phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 
(mTOR) inhibitor being developed for use in adult patients with advanced solid tumors.
1.2. Indication – Amendment 5
PF-05212384 in combination with cisplatin is being developed for use in adult woman with 
metastatic or locally-recurrent/advanced triple hormone-receptor negative breast cancer 
(TNBC) in first- through third-lines of therapy.
1.3. Background 
1.3.1. PI3K/mTOR 
PI3Ks constitute a lipid kinase family involved in the regulation of diverse cellular processes, 
including proliferation, survival, cytoskeletal organization, and glucose transport.1  PI3K 
enzymes catalyze the formation of the second messenger phosphatidylinositol (3, 4, 
5)-trisphosphate (PIP3), which activates many target proteins, most notably 
phosphoinositide-dependent kinase-1 (PDK1).  The downstream targets of these protein 
kinases, such as mammalian target of rapamycin (mTOR), BCL2-associated agonist of cell 
death (BAD) and forkhead box O proteins (FOXOs), mediate most of the proliferation, 
growth and survival signaling from PI3Ks (Figure 3).2,3 Activation of the PI3K pathway has 
been implicated in a wide variety of human cancers.  Mutations in 
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), the gene 
encoding the catalytic subunit of PI3K, are very common in human cancers, having been 
observed in prostate, and colorectal tumors, among others.  Phosphatase and tensin homolog 
(PTEN) deletion, leading to activation of Akt has been observed in many types of 
malignancies including prostate cancer, breast cancer, and glioma.4
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Figure 3.
PI3K/mTOR and EGFR Signaling Pathways
Inhibitors of mTOR are in development for the treatment of cancers, most of these agents are 
analogs of rapamycin, which specifically inhibit the activity of the TORC1 complex.5,6  
Analogs of rapamycin such as CCI-779 (temsirolimus) and RAD-001 (everolimus) have been 
shown to provide benefit to patients for the treatment of renal cell carcinoma.  However, 
specific inhibition of TORC1 results in a feedback stimulation of Akt and thus inhibition of 
TORC1 alone may be inferior to inhibition of PI3K and both TORC complexes.7
The role of human epidermal growth factor receptor (HER) family members HER-1 
(epidermal growth factor receptor (EGFR)), HER-2 (neu/c-erb-2), and HER-3 in many 
cancer types is well documented.  One or more of the members of this receptor family are 
expressed in over 90% of solid tumors and approximately 60% of those tumors possess 
abnormalities in this family that potentially contribute to their neoplastic phenotype.8,9  
Over-expression of the HER-2 gene is associated with aggressive neoplastic phenotype and 
reduced survival in patients with breast cancer.  Over-expression of HER-2 has also been 
correlated with poor prognosis and sensitivity to the anti-HER-2 monoclonal antibody, 
trastuzumab, in patients with other tumor types including lung, gastric, ovarian, and 
colorectal carcinomas.  EGFR over-expression or aberrant function has been widely noted in 
lung, renal, prostate, breast, head and neck, colorectal, and other malignancies.10,11,12  The 
level of EGFR expression appears to be one factor affecting tumor proliferation, 
invasiveness, and angiogenesis, and relates adversely to prognosis. In addition, EGFR 
mutations have been identified which appear to drive tumorigenesis and which determine 
sensitivity to EGFR targeted agents such as gefitinib.13,14  HER family members are 
considered clinically validated targets based on successful development of both biologics and 
small molecule inhibitors including trastuzumab, lapatanib, erlotinib, cetuximab, and 
panitumumab.
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The PI3K pathway is associated with resistance to a variety of anti-tumor agents.  This has 
been described pre-clinically with cytotoxic chemotherapeutic agents with varying
mechanisms of action including taxanes and deoxyribonucleic acid (DNA)-damaging 
agents.15,16  In the clinic, activated PI3K in tumors has been correlated with decreased 
response to therapy and worse clinical outcomes.17,18,19 In addition to resistance to cytotoxic 
agents, there is also evidence of PI3K signaling affecting sensitivity of cells to EGF signaling 
inhibitors.  Specifically, the activation of PI3K in tumors has been associated with a worse 
outcome in patients with HER2-positive gastric cancer treated with anti-HER2 agents.18  
Finally, pre-clinical studies have described the role of the PI3K pathway in EGFR activation 
in glioblastoma multiforme (GBM) and non-small cell lung cancer (NSCLC) cells and have 
demonstrated that PI3K inhibitors can reverse resistance to EGFR inhibitors in tumor 
models.20
1.3.2. PF-05212384
PF-05212384 is an ATP-competitive, pan class I PI3K inhibitor, with an IC50 of 0.4 nM
against PI3Kα and against mTOR with antiproliferative activity in culture and anti-tumor 
activity in xenograft models.  It is intended to be dosed once weekly by intravenous (IV) 
infusion.
1.3.2.1. Preclinical Data for PF-05212384
PF-05212384 has been shown to cause tumor growth inhibition as well as tumor regressions 
in a variety of human xenograft tumor models (Table 1).  In vivo biomarker studies 
demonstrated that PF-05212384 suppressed PI3K/mTOR pathway signaling as evidenced by 
decreased phosphorylation of AKT.  These studies were done in MDA361 (human breast) 
tumor xenografts propagated in nude mice.  In this model, pAKT at position T308 was 
suppressed for 8 hours with PF-05212384 at a dose of 25 mg/kg.  Additionally, increased 
cleaved poly ADP ribose polymerase (PARP), a marker for apoptosis, was observed which 
correlated  with the tumor regression.
Table 1.
Tumor Growth Inhibition with Single Agent PF-05212384
Cell Line
Tumor Type
Effects of PF-05212384 Treatment
LST147T
Colon
Growth inhibition
HCT116
Colon
Growth inhibition
BT-474
Breast
Growth inhibition
MDAMB361
Breast
Regression
A549
Non-small cell lung
Growth inhibition
H1975
Non-small cell lung
Growth inhibition
U87MG
Glioma
Stasis
PDX-OV1002
Ovary
Stasis
PDX-HOX516
Ovary
Stasis
MFE296
Endometrial
Stasis
AN3CA
Endometrial
Stasis
MFE280
Endometrial
Regression
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1.3.3. PF-05212384 Clinical Experience
PF-05212384 has been evaluated in one completed Phase 1 clinical trial in adult patients with 
solid cancer, and is being evaluated in two ongoing clinical trials (one Phase 1b study in 
combination with irinotecan, and one Phase 2 study in endometrial cancer as single agent).  
1.3.3.1. Phase 1 Study of PF-05212384 Single Agent in Patients with Advanced Solid 
Tumors (B2151001)
The first-in-human (FIH) Phase 1 trial, B2151001 evaluated the safety and pharmacokinetics 
(PK) of single agent PF-05212384 in patients with advanced solid tumors.  PF-05212384 
doses ranging from 10 mg to 319 mg weekly were administered to a total of 77 patients using 
a continuous reassessment method (CRM) to estimate the maximum tolerated dose (MTD).  
The MTD was decared to be 154 mg, a dose level at which patients received a median 
number of 7 weekly doses (range 1-24).  In general treatment with single agent PF-05212384 
was well tolerated over multiple cycles of treatment. Table 2 includes the number of dose 
limiting toxicities (DLTs) that occurred during the active treatment phase with PF-05212384.  
Most DLTs occurred at dose levels above the MTD.
Treatment-related adverse events are summarized in Table 3 and Table 4.  The most common 
treatment-related AEs at the MTD (154 mg) were mucosal inflammation and nausea, which 
were reported in nearly half of the patients (42.9% and 40.5%, respectively), followed by 
hyperglycemia (26.2%), vomiting (23.8%), and asthenia, decreased appetite, and fatigue 
(21.4% each). Dysgeusia (19.0%), AST increase, and diarrhea (14.3% each) were also 
frequent adverse events associated with treatment with PF-05212384.  To be noted, although 
hyperglycemia was reported as an AE in 26.2% of patients at the MTD, the chemistry data 
showed hyperglycemia in 78.6% of patients treated at the MTD of PF-05212384, although 
mainly of Grades 1 and 2 (71.4% of all patients treated at the MTD); 3 (7.1%) patients had 
Grade 3 hyperglycemia.
Three patients discontinued treatment with PF-05212384 due to treatment related adverse 
events (one patient with increased ALT at the 319 mg dose level, and two patients with 
mucositis at the 222 mg and 319 mg dose levels, respectively).  
Table 2.
Phase 1 Study B2151001: Dose Limiting Toxicities by Preferred Term and 
Dose
Dose Limiting Toxicity by Preferred Term
Dose Level of PF-05212384
154 mg 
(n=42)
MTD
222 mg 
(n=7)
266 mg 
(n=8)
319 mg 
(n=4)
Mucosal inflammation Grade 3
1
3
2
1
ALT Grade 3
1
1
AST Grade 3
1
Stomatitis Grade 2
1
Rash Grade 3
2
1
Hyperglycemia Grade 3
1
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Table 3.
Phase 1 Study B2151001: Treatment-Related, Treatment Emergent Adverse 
Events by MedRA Preferred Term in ≥2 Patients; PF 05212384 154 mg Dose 
Level (MTD) – All CTCAE Grades
PF-05212384 154 mg
N=42
Adverse Event by Preferred Term
n (%)
Adverse Event by Preferred Term
n (%)
Mucosal inflammation
18 (42.9)
Dehydration
3 (7.1)
Nausea
17 (40.5)
Dermatitis acneiform
3 (7.1)
Hyperglycemia
11 (26.2)
Dry skin
3 (7.1)
Vomiting
10 (23.8)
Hypercholesterolemia
3 (7.1)
Asthenia
9 (21.4)
Lymphopenia
3 (7.1)
Decreased appetite
9 (21.4)
Rash
3 (7.1)
Fatigue
9 (21.4)
Abdominal pain upper
2 (4.8)
Dysgeusia
8 (19.0)
Arthralgia
2 (4.8)
Aspartate aminotransferase 
increased
6 (14.3)
Blood alkaline phosphatase increased
2 (4.8)
Diarrhea
6 (14.3)
Dizziness
2 (4.8)
Alanine aminotransferase increased
5 (11.9)
Hypercalcemia
2 (4.8)
Pyrexia
5 (11.9)
Hyperhidrosis
2 (4.8)
Stomatitis
5 (11.9)
Insomnia
2 (4.8)
Dry mouth
4 (9.5)
Oral herpes
2 (4.8)
Hypertriglyceridemia
4 (9.5)
Proctitis
2 (4.8)
Constipation
3 (7.1)
Pruritus
2 (4.8)
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, N = total number of patients, 
n = number of patients meeting prespecified criteria
Table 4.
Phase 1 Study B2151001: Summary of Treatment-Related, 
Treatment-Emergent Adverse Events by MedRA Preferred Term; 
Maximum CTCAE Grades 3, 4, and 5
Adverse Event Preferred Term
Grade 3
Grade 4
Grade 5
n (%)
n (%)
n (%)
PF-05212384 (154 mg; N=42)
Any AEs
10 (23.8)
0
0
Alanine aminotransferase increased
3 (7.1)
0
0
Aspartate aminotransferase increased
2 (4.8)
0
0
Asthenia
1 (2.4)
0
0
Blood alkaline phosphatase increased
1 (2.4)
0
0
Hyperglycemia
1 (2.4)
0
0
Hypersensitivity
1 (2.4)
0
0
Mucosal inflammation
2 (4.8)
0
0
Nausea
1 (2.4)
0
0
Pyrexia
1 (2.4)
0
0
Stomatitis
1 (2.4)
0
0
Urticaria
1 (2.4)
0
0
Vomiting
1 (2.4)
0
0
MedDRA (version 15.1) coding dictionary applied.
Abbreviations:  AEs = adverse events, CTCAE = Common Terminology Criteria for Adverse Events, 
MedDRA = Medical Dictionary for Regulatory Activities, N = Total number of patients, n = number of 
patients meeting prespecified criteria
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Analysis of plasma samples taken after IV administration indicated that PF-05212384 is 
eliminated with a half-life of 40-65 hours at the highest dose.  While the data appeared to 
indicate that the half life increased with dose, it is considered that this finding was likely to 
be an artifact of poor assay sensitivity at lower doses.  The estimated half life is similar 
across doses from 89 to 319 mg weekly.  Clearance of PF-05212384 is linear with dose, and 
distribution is relatively high.  Plasma concentrations of PF-05212384 exceeded the 50% of 
maximal inhibition (IC50) of PI3K and mTOR dependent phosphorylation events for 
approximately 70 hours at doses of 89 and 154 mg, and for ≥120 hours at the 266 mg and 
319 mg dose.  The target concentration was based on projected human plasma concentration 
from xenograft models where analysis of xenograft tumor tissue showed a greater than 50% 
suppression of pAKT and an induction of cleaved PARP, an indicator of cellular 
commitment to apoptosis.  
To date, partial responses (PR) have been observed in 2 patients (NSCLC with liver and lung 
metastases [n=1] and granular cellular tumor of the ovary with peritoneal and pleural 
metastases [n=1]) and 19 patients have experienced stable disease (SD), with 6 experiencing 
SD >6 months.
1.3.3.2. Phase 1 Study of PF-05212384 in Combination with Irinotecan in Patients with 
Advanced Solid Tumors (B1271002)
A Phase 1b study is ongoing which includes the assessment of escalating doses of 
PF-05212384 in combination with irinotecan (180 mg/m2) every 2 weeks of 28-day cycles.  
To-date, 13 patients have been treated with PF-05212384 at doses of 95 mg/week (n=3), 
110 mg/week (n=6), and 130 mg/week (n=4).  Two patients out of 4 experienced 
dose-limiting toxicities, Grade 4 febrile neutropenia (n=1) and Grade 3 fatigue (n=1), while 
receiving 130 mg/week of P-05212384 plus irinotecan 180 mg/m2 every 2 weeks.  Based on 
these findings, the MTD for PF-05212384 when combined with irinotecan 180 mg/m2 every 
2 weeks has been determined to be 110 mg/week.  The most common treatment-related AEs 
reported in the 6 patients treated at the MTD include nausea in 3 patients and alopecia, 
diarrhea, proteinuria, maculopapular rash and vomiting in 2 patients each.  All of the events 
were Grade 1-2.  One patient with advanced colorectal cancer (CRC), previously treated with 
irinotecan, was treated at the PF-05212384 95 mg/week dose cohort and experienced a PR
(of 6 cycles in duration).  A second patient with CRC previously treated with irinotecan 
experienced 10% tumor shrinkage and remained on study for 6 months.  One patient with 
pancreatic cancer had tumor shrinkage of 5% and remained on study treatment for 4 months, 
and one patient with pancreatic cancer had tumor shrinkage of 27% and SD for a duration of 
9 cycles. 
1.3.3.3. Phase 2 Study of PF-05212384 Single Agent in Patients with Advanced 
Endometrial Cancer (B1271004)
Single agent PF-05212384 is currently being evaluated in patients with advanced endometrial 
cancer in Phase 2 study B1271004.  PF-05212384 is being administered at the MTD dose of 
154 mg/week.  As of February 5, 2013, 20 patients have been randomized to the 
PF-05212384 arm of the study.  Four patients have achieved clinical benefit as defined by 
lack of disease progression in first 16 weeks.  The preliminary safety profile of PF-05212384 
from B1271004 is similar to that from Study B2151001.
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Complete information for this compound may be found in the Single Reference Study 
Document (SRSD), which for this study is the Investigator’s Brochure.
1.3.4. Docetaxel
Docetaxel is a semisynthetic taxane whose mechanism of action is to promote tubulin 
assembly in microtubules and to inhibit their depolymerization which causes cells to arrest in 
mitosis and eventually undergo apoptosis.  Docetaxel is effective in a wide variety of solid 
tumors and is indicated as a single agent or in combination with other chemotherapeutic 
agents for the treatment of patients with breast, lung, hormone-refractory prostate, gastric, 
and head and neck tumors. Docetaxel doses range from 60-100 mg/m2 depending on the 
indication and are administered as an infusion every three weeks.  Notable toxicities include 
fluid retention and hypersensitivity reactions.15  Premedication is required to minimize these 
adverse event and typically consists of dexamethasone 8 mg twice a day (bid) given for 
3 days starting 1 day prior to docetaxel administration.   Docetaxel is most commonly 
associated with myelosuppression and gastrointestinal adverse events.  
In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 
isoenzyme and its metabolism may be modified by the concomitant administration of 
compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4.  Docetaxel is
primarily eliminated by fecal excretion. 
Complete information for docetaxel may be found in the SRSD, which for this study is the 
European Union (EU) European Medicines Agency (EMA)-approved Summary of Product 
Characteristics (SmPC) for Taxotere®.
1.3.5. Cisplatin
Cisplatin reacts in vivo by binding to and causing crosslinking of DNA, ultimately triggering 
apoptosis.  It is used widely as a single agent or in combination with other agents to treat 
various types of cancer including testicular, bladder, small cell lung, ovarian, and TNBC.  
Cisplatin doses range from 50-100 mg/m2 administered IV every 3-4 weeks.  In order to 
mitigate nephrotoxic risks, pre- and post-dose hydration is often used as described in the 
product label.  
Notable toxicities include renal insufficiency, myelosuppresion, nausea and vomiting. 
Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to 
chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to 
enzyme-catalyzed metabolism.  Cisplatin is not metabolized hepatically.  Cisplatin is 
excreted through the urine.
Complete information for cisplatin may be found in the SRSD, which for this study is the 
United Kingdom (UK) approved Summary of Product Characteristics (SmPC) from Hospira 
UK Ltd.
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1.3.5.1. PF-05212384 Plus Cisplatin in Patients with TNBC
The rationale for combining cisplatin with PF-05212384 in patients with metastatic or 
locally-recurrent/advanced triple hormone-receptor negative breast cancer (TNBC) is 
two-fold: First, there is amplified genomic instability of TNBC tumor cells, leading to an 
increased vulnerability of TNBC to DNA-damaging agents, such as cisplatin.  TNBC tumor 
cells harbor activating mutations in the PIK3CA gene, making these cells excellent targets 
for inhibition of the PI3K pathway using pathway inhibitors, such as PF-05212384.46
In addition, some fraction of TNBC tumor cells (~20%) harbor mutations in the DNA repair 
genes breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2), suggesting a functional deficit 
in the process of homologous recombination repair (HRR) of DNA. The inability to repair 
DNA efficiently makes these cells particularly susceptible to the DNA cross-link strand 
breaks caused by platinating agents, like cisplatin.40,46
The use of cisplatin in combination regimens in patients with TNBC has shown improved 
rates of tumor response in both the neoadjuvant and metastatic setting.40,50  As such, recent 
National Comprehensive Cancer Network® (NCCN) guidelines for treatment of metastatic 
TNBC have included platinum salts, such as cisplatin.51
The above information provides a sound rationale for combining PF-05212384 with cisplatin 
in the treatment of patients with metastatic TNBC.
1.3.6. Dacomitinib (PF-00299804)
The investigational agent dacomitinib is an orally available, selective ATP-competitive 
irreversible small-molecule inhibitor of Human Epidermal Growth Factor Receptor (HER, 
erbB) family receptor tyrosine kinases (RTKs).  This family of RTKs includes the epidermal 
growth factor receptor (EGFR, HER-1), HER-2 receptor (erbB2), and HER-4 (erbB4) 
receptor and their oncogenic variants (ie, EGFR exon 19 deletion, EGFR L858R point 
mutation, and EGFR T790M mutation).  Dacomitinib inhibits the tyrosine kinase activity of 
the HER family through binding at the adenose triphosphate (ATP) binding site, which 
results in covalent modification of a cystine in the ATP binding pocket. HER-1 and -2 
receptor mutations and amplification have been investigated as possible favorable predictors 
of clinical efficacy and, in particular, it has been shown that patients with certain mutations 
of EGFR (exon 19 deletions and exon 21 L858R mutations) have significant benefit from 
EGFR Tyrosine Kinase Inhibitor (TKI).  Dacomitinib is being developed for patients 
with previously treated, locally advanced or metastatic non-small cell lung cancer
(NSCLC).
Dacomitinib given orally without food in the FIH dose escalation study, A7471001, was 
absorbed with a median time to the maximum observed concentration (Tmax) ranging from 
4 to 24 hours.  There was no evidence of a clinically relevant effect of antacid administration 
on Cmax and AUCinf (defined as area under the plasma concentration-time profile from time 
zero to infinity time) of dacomitinib.  In general, the mean Cmax and AUC of PF-00299894 
increased with dose at the dose range evaluated.  After continuous once daily oral dose (QD) 
for 14-days, the mean AUC accumulation of dacomitinib ranged from 4.39 to 6.18-fold, 
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suggesting a long t½.  Inter-patient variability in PK exposure parameters varied from 
14-65%.  There was no evidence of increasing trough concentrations with time when 
examining available predose concentrations on Cycle 2 Day 1, 8, and 14 in a limited number 
of patients (n=2-4) at 45 mg.  To date, the terminal t½ has been characterized in patients at 
45 mg, and ranged from 75 to 110 hour with a mean of approximately 85 hours.  
Dacomitinib is metabolized in part by cytochrome P450 2D6 (CYP2D6) and an active 
metabolite, PF-05199265, is formed.  Dacomitinib also inhibits the CYP2D6 metabolic 
pathway.  Collectively results from clinical studies suggest that dacomitinib may increase 
exposure of other drugs primarily metabolized by CYP2D6 and therefore administration of 
drugs which are highly dependent on CYP2D6 metabolism may require dose adjustment, or 
substitution with an alternative medication.  Dacomitinib is mainly eliminated by fecal 
excretion.
Dacomitinib is currently in Phase 3 development in advanced NSCLC.  As of 16 May 2012, 
1503 patients with advanced cancer have been enrolled and treated in 13 clinical trials 
evaluating the safety, efficacy and pharmacokinetics of dacomitinib.  Of these 1503 patients, 
579 patients were administered dacomitinib as single agent, 466 patients received either 
dacomitinib or placebo as double-blinded therapy, 293 patients received either dacomitinib or 
erlotinib as double-blinded therapy, 71 patients received dacomitinib in combination with 
CP-751,871 (figitumumab).  Patients have also been treated with dacomitinib in combination 
with crizotinib.
Complete information for dacomitinib may be found in the SRSD, which for this study is the 
Investigator’s Brochure (IB).
Overall, the adverse events associated with dacomitinib single agent have been considered 
manageable, reversible, and consistent with class-effects associated with EGFR TKIs.  
Table 5 provides a summary of the most common treatment-related AEs reported for single 
agent dacomitinib (all patients, all doses, all grades).  
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Table 5.
Summary of Treatment-Related Adverse Events in ≥10% of Patients 
Treated with Single-Agent Dacomitinib
Adverse Drug Reaction
All Grades
N=526
N (%)
Diarrhea
435 (82.7)
Dermatitis acneiform
309 (58.7)
Fatigue
224 (42.6)
Dry skin
186 (35.4)
Stomatitis
171 (32.5)
Paronychia
136 (26)
Decreased appetite
166 (31.6)
Nausea
155 (29.5)
Paronychia
138 (26.2)
Pruritus
115 (21.9)
Vomiting
110 (20.9)
Cough
98 (18.6)
Dyspnoea
92 (17.5)
Mucosal inflammation
91 (17.3)
Rash
91 (17.3)
Palmar-plantar erythrodysaesthesia syndrome
78 (14.8)
Weight decreased
70 (13.3
Constipation
68 (12.9)
Skin fissures
66 (12.5)
Epistaxis 
62 (11.8)
Exfoliative rash
62 (11.8)
Back pain
58 (11)
Abdominal Pain
55 (10.5)
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Table 6 provides a summary of the most common treatment-related AEs reported following 
treatment with dacomitinib at 45 mg QD in patients with advanced NSCLC.
Table 6.
Summary of Treatment Related Adverse Events in ≥10% of Patients with 
NSCLC Treated with Dacomitinib at a Dose of 45 mg QD
Adverse Drug Reaction
All Grades
N=262
N (%)
Grades ≥3
N=262
N(%)
Diarrhea
212 (80.9)
29 (11.1)
Dermatitis acneiform
170 (64.9)
19 (7.3)
Fatigue
97 (37)
14 (5.3)
Decreased appetite
81 (30.9)
3 (1.1)
Stomatitis
81 (30.9)
3 (1.1)
Dry skin
80 (30.5)
1 (0.4)
Paronychia
75(28.6)
10 (3.8)
Nausea
69 (26.3)
3 (1.1)
Pruritus
50 (19.1)
4 (1.5)
Mucosal inflammation
46 (17.6)
2 (0.8)
Exfoliative rash
35 (13.4)
4 (1.5)
Cough
44 (16.8)
7 (2.7)
Vomiting
43 (16.4)
7 (2.7)
Weight decreased
36 (13.7)
0 (0)
Exfoliative rash
35 (13.4)
4 (1.5
Constipation
32 (12.2)
1 (0.4)
Palmar-plantar erythrodysaesthesia syndrome
30 (11.5)
1 (0.4)
1.3.7. Study Rationale
Signaling through the PI3K pathway is associated with resistance to a variety of anti-tumor 
agents.  This has been described pre-clinically with cytotoxic chemotherapeutic agents with 
varying mechanisms of action including taxanes, and DNA-damaging agents.22,23  In the 
clinic, activated PI3K pathway in tumors has been correlated with decreased response to 
therapy and worse clinical outcomes.18,19
In addition to resistance to cytotoxic agents, there is also evidence of PI3K signaling 
affecting sensitivity of cells to EGF receptor family signaling inhibitors.  Specifically, the 
activation of PI3K in tumors has been associated with a worse outcome in patients with 
HER2-positive gastric cancer treated with anti-HER2 agents.24 In addition, pre-clinical 
studies have described the role of the PI3K pathway in EGFR activation in glioblastoma 
multiforme (GBM) and NSCLC cells and have demonstrated that PI3K inhibitors can reverse 
resistance to EGFR inhibitors in tumor models.20
Collectively, these findings suggest that PI3K/mTOR inhibitors may increase the efficacy of
both chemotherapeutic agents which are considered standard of care (SOC) for the treatment 
of several solid tumors and dacomitinib which has shown clinical activity in several tumor 
types.  
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1.3.7.1. Rationale for Combinations
1.3.7.1.1. Docetaxel
Docetaxel is a microtubule inhibitor which is active in a number of human solid tumors.  In 
pre-clinical in vitro studies, the combination of docetaxel and a PI3K inhibitor resulted in 
additive and even synergistic activity in a variety of human cancer cell lines.  In vivo
experiments revealed enhanced anti-tumor efficacy with the combination.16  Non-clinical 
experiments in human NSCLC H1975 and H1650 xenograft models have demonstrated that 
the combination of PF-05212384 and docetaxel is more effective than either drug alone 
(Figure 4).  Finally, patients with tumors with activated PI3K/Akt signaling have been shown 
to be less responsive to a variety of chemotherapeutic agents including docetaxel and 
paclitaxel.17,18  The pre-clinical findings together with the clinical observations, suggest that 
the addition of PF-05212384 to docetaxel may lead to enhanced antitumor effects in patients.
Figure 4.
Tumor Growth Inhibition of PF-05212384 in Combination with Docetaxel 
Versus either compound alone in H1975 Lung Xenograft Model
H1975
15
20
25
30
35
200
400
600
800
1000
Control
PF-05212384 10mg/kg 2xwkly
Docetaxol 10mg/kg qwk
PF384+Docetaxol
Days
Median  Tumor Volume (mm3)
1.3.7.1.2. Cisplatin
Cisplatin is an alkylating agent which cross-links DNA.  Preclinically, the combination of 
PI3K inhibitor and cisplatin resulted in synergistic anti-tumor activity in human ovarian 
cancer cell models.15  Furthermore, the combination of PF-05212384 and cisplatin 
demonstrated increased anti-tumor efficacy in a breast PDX xenograft model (PJC10).  Since 
single-agent cisplatin is active in patients with triple-negative breast cancer (TNBC) the
combination of PF-05212384 and cisplatin may be an extremely effective regimen in an area 
of great medical need.24  Cisplatin is also used in combination with gemcitabine in a number 
of tumor types such as urothelial transitional cell cancers (TCC), NSCLC, and biliary tract 
tumors and in combination with other chemotherapeutic agents in ovarian cancer (OC).  
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Thus, based on the preclinical evidence of additive or synergistic activity, once the clinical 
safety and tolerability of the combination of PF-05212384 and cisplatin has been established, 
it may be possible to consider replacing gemcitabine with PF-05212384 in these regimens.  
1.3.7.1.3. Dacomitinib
EGFR and HER2 are important mediators of tumorogenesis in a number of tumors and PI3K 
is a critical EGFR-dependent effector of downstream signaling.  Activation of the PI3K 
pathway has been shown to be associated with resistance to HER2 inhibition.  This is 
supported by the observation that in patients with HER2+ gastric cancer, activated PI3K 
signaling predicts for a worse clinical outcome.25  Further evidence of cross-talk between the 
EGFR and PI3K pathways exists in glioblastoma and  NSCLC models.20,26 In a preclinical
NSCLC model, the addition of a PI3K inhibitor to gefitinib was shown to overcome 
resistance to gefitinib.20  Finally, in the H1975 lung xenograft model, tumor growth 
inhibition was observed for the combination of PF-05212384 with neratinib, a EGFR and 
HER2 inhibitor suggesting that the combination with the pan-HER inhibitor dacomitinib 
might also be beneficial (Figure 5).27  
Figure 5.
Tumor Growth Inhibition of PF-05212384 in Combination with HKI-272 
(irreversible Her2 inhibitor) in H1975 Lung Xenograft Model
These data support the evaluation of the combination of PF-05212384 and dacomitinib.
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1.3.7.2. Rationale for PF-05212384 Doses
In Phase 1 study B2151001, single agent PF-05212384 at doses ranging from 10 mg to 
319 mg weekly (QW) were evaluated in 77 patients with advanced solid tumors.  The MTD 
was identified as 154 mg QW.  In study B1271002, PF-05212384 doses of 95, 110, and 
130 mg/week were evaluated in combination with irinotecan 180 mg/m2 every 2 weeks; the 
MTD of PF-05212384 was 110 mg/week when dosed in combination with irinotecan.
In the current trial, the PF-05212384 starting dose in all 3 treatment arms will be 90 mg/week 
which is 58% of the MTD for single agent PF-05212384 and slightly lower than the lowest 
dose evaluated in Phase 2 study B1271002 investigating PF-05212384 in combination with 
irinotecan.  In the Phase 1 FIH trial (B2151001), PF-05212384 dose of 89 mg/week (n=4) 
was found to result in drug concentrations above the target concentration for approximately 
70 hours.  
1.3.7.3. Rationale for Docetaxel, Cisplatin and Dacomitinib Starting Doses
In Arm A, the starting dose of docetaxel will be 75 mg/m2 every 3 weeks. This is the dose 
recommended in combination with doxorubicin and cyclophosphamide for breast cancer, in 
combination with prednisone in hormone refractory prostate cancer, and as single agent in
NSCLC.28
In Arm B, the starting dose of cisplatin will be 75 mg/m2 every 3 weeks which is the dose 
often used when it is administered as an every 3 week regimen in combination with 
docetaxel, gemcitabine, or pemetrexed.29,30,31
In Arm C, the starting dose of dacomitinib will be 30 mg which is 67% of the MTD for 
single agent dacomitinib when administered orally once daily on a continuous dosing 
schedule.  This starting dose was selected given the potential for overlapping toxicity with 
PF-05212384, such as mucositis and rash.  In the dacomitinib FIH trial in patients with 
advanced tumors, among 111 patients treated in dose-escalation, 13 were treated at the 
30 mg/day dose level.  One DLT (mucositis) was observed in this group.  The safety profile 
in the specific dose levels was not reported.32 As described in the IB, the 30 mg dose has 
only been evaluated in a small number patients in subsequent trials however the 30 mg dose 
is generally better tolerated than the 45 mg dose. 
During the course of the trial, dose reductions for each combination will be permitted in 
individual patients who cannot tolerate the starting dose (Section 5.2.5).
1.4. Overall Risk Benefit Assessment
Pfizer considers that the results of the nonclinical toxicity and safety pharmacology studies, 
together with the clinical experience obtained to date with PF-05212384 support the 
continued development of PF-05212384 in combination with other anti-tumor agents.  The 
tumor types in which these combinations will likely be used, all represent areas of high 
medical need. 
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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives – Original Protocol through Amendment 4
Primary Objective
•
To assess the safety and tolerability and to estimate the MTD of the following 
combinations in patients with advanced solid tumors:
•
Arm A: PF-05212384 and docetaxel.
•
Arm B: PF-05212384 and cisplatin.
•
Arm C: PF-05212384 and dacomitinib.
Secondary Objectives
•
To evaluate the overall safety profile.
•
To assess the effects of PF-05212384 on the pharmacokinetics of docetaxel, cisplatin 
and dacomitinib and vice versa in Arms A, B, and C respectively.
•
To evaluate possible biomarkers of efficacy (eg, KRAS mutation) and 
pharmacodynamic (PD) effects in paired tumor biopsies (eg, pAkt levels) and serum 
(eg, insulin levels).
•
To characterize the effects of the combinations on the potential to prolong the QTc
interval.
•
To document anti-tumor activity.
2.2. Endpoints – Original Protocol through Amendment 4
Primary Endpoint
•
Dose Limiting Toxicity (DLT).
Secondary Endpoints
•
Adverse Events as characterized by type, frequency, severity (as graded by NCI 
CTCAE v.4.03), timing, seriousness and relationship to study therapy.
•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
•
Vital sign abnormalities.
•
Single and multiple dose PK parameters of PF-05212384, and other anti-tumor agents 
(docetaxel, cisplatin or dacomitinib) alone and together, respectively.
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•
Gene sequence data (eg, PIK3CA, KRAS) and levels of PI3K pathway protein 
biomarkers (eg, pAkt, PTEN, circulating insulin).
•
QTc interval.
•
Objective tumor response, as assessed using the Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1.
2.3. Objectives - Safety and Efficacy Expansion in Patients with TNBC 
Primary Objective
•
To evaluate the anti-tumor activity of PF-05212384 plus cisplatin in patients with 
TNBC.
Secondary Objectives
•
To continue to evaluate the overall safety profile of the combination of PF-05212384 
plus cisplatin.
•
To characterize single and multiple dose pharmacokinetics following IV 
administration of PF-05212384.
•
To characterize the effects of the combinations on the potential to prolong the QTc
interval.
•
To evaluate additional anti-tumor activity.
•
To assess patient reported outcomes (PRO) of global quality of life (QOL) and
disease/treatment-related symptoms of advanced breast cancer.
 
 
2.4. Endpoints - Safety and Efficacy Expansion in Patients with TNBC
Primary Endpoint
•
Objective response (OR) as assessed by the Investigator using RECIST version 1.1.
Secondary Endpoints
•
Adverse Events as characterized by type, frequency, severity (as graded by NCI 
CTCAE v.4.03), timing, seriousness and relationship to study therapy.
&&,
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•
Laboratory abnormalities as characterized by type, frequency, severity (as graded by 
NCI CTCAE v. 4.03) and timing.
•
Single and multiple dose PK parameters of PF-05212384.
•
QTc interval.
•
Clinical Benefit Response (CBR), Duration of Response (DR) and PFS (as assessed 
using RECIST version 1.1).
•
Time to deterioration in global QOL.
•
Change from baseline in global QOL and disease/treatment-related symptoms.
 
 
3. STUDY DESIGN
This is a Phase 1b, three-arm, open-label, multi-center, multiple dose, dose escalation, safety,
tolerability, pharmacokinetic and pharmacodynamic study of PF-05212384 in combination 
with anti-tumor agents in sequential cohorts of adult patients with select advanced solid 
tumors.  Successive cohorts of patients will receive selected doses of PF-05212384 in 
combination with selected doses of chemotherapeutic agents or dacomitinib in 3 independent 
arms on an outpatient basis.  Based on the tolerability of PF-05212384 at higher doses in 
other (monotherapy) studies, the study will test increasing doses of PF-05212384 in 
combination with docetaxel, cisplatin, and/or dacomitinib in order to select the best dose to 
administer in the MTD expansion portion of the study.
A modified toxicity probability interval (mTPI) method with adjustment based on observed 
DLT rate will be used to guide the dose assignment in Arms A and B.33,34  The actual dose 
selected for the next cohort will take into account the recommended dose by using the 
adjusted mTPI method as well as safety data other than DLTs.  In Arm C in order to evaluate 
concurrent doses of dacomitinib in combination with two concurrent doses of PF-05212384, 
a zone-based design will be utilized, which is a modified 3+3 design that potentially allows 
opening of more than one dose level at the same time.35 In all arms, dose escalation will 
proceed until an MTD (or two MTDs) is declared, or the Maximum Allowable Dose is 
reached.
On April 1, 2015, Pfizer Inc. decided to stop enrolment in Arms A and C of the B2151002 
clinical trial.  Patients previously identified for enrolment in Arm A and C were permitted to 
enter the study after notification of the decision.  Due to closure, the MTD of those 
combinations will not be established.  All references to objectives, endpoints, study design, 
assessments, etc. and analysis of data in Arm A and C will be limited to the number of 
&&,
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patients treated up to the enrolment discontinuation date for each Arm (June 10, 2015 for 
Arm A and 06 July 2015 for Arm C).  The decision is based on the company’s change in 
prioritization for the portfolio and is not due to any safety/efficacy concerns or regulatory 
interactions.  
For Arm B, the study was originally designed as a dose escalation study with no expansion 
cohorts.  However, Protocol Amendment 5 includes the rationale and description for the 
safety and efficacy expansion with PF-05212384 plus cisplatin in patients with metastatic or 
locally-recurrent/advanced triple hormone-receptor negative breast cancer (TNBC). A total 
of 21 patients were enrolled in Arm A, 33 in Arm B and 33 patients in Arm C in the dose 
escalation. Approximately 124 patients are expected overall including the safety and 
efficacy expansion. Pharmacodynamic studies will be performed in paired tumor biopsies, 
when clinically feasible, to evaluate PI3K and mTOR pathway inhibition at the PF-05212384 
doses used in the MTD.  Paired biopsies that are obtained during dose escalation and 
expansion will also be evaluated for modulation of PI3K signaling.
Each of the treatment arms are restricted to patients with tumor types for which the 
combination partner is either considered standard-of-care, or in the case of dacomitinib, are 
indications which have been shown to be sensitive. 
Figure 6.
Original Overall Study Design
CRPC: Castrate resistant prostate cancer; NSCLC: Non-small cell lung cancer; ABC: Advanced breast cancer; 
TCC: Transitional cell cancer; TNBC: Triple negative breast cancer; OC: ovarian cancer; HNSCC: Head and 
neck squamous cell cancer; BC: Breast cancer.
OC
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To understand the single-dose safety and single dose PK of the study drug, a lead in period 
will be included.  A single lead-in dose of PF-05212384 will be given either 7 days prior to 
Cycle 1 Day 1 (Arms A and B) or 14 days prior to Cycle 1 Day 1 (Arm C). The lead in 
period duration, subsequent doses, regimens and PK time-points may be modified based on 
the PK profile observed during the lead in period.  Patients will then receive study treatment 
on an outpatient basis in 21 day cycles.  
Treatment with study drug will continue until progression of disease, uncontrollable toxicity, 
a decision by the patient or Investigator to discontinue treatment, or the study is terminated.  
Patients experiencing toxicity or a DLT may be managed with dose modification or 
discontinuation.  If a patient discontinues PF-05212384 or the combination partner (cisplatin, 
docetaxel, or dacomitinib) due to toxicity which is specific to either agent, continuation of 
patient treatment within the study with single agent PF-05212384, cisplatin, docetaxel, or 
dacomitinib will be discussed with the Sponsor on a case-by-case basis.  
The proposed doses, schedule(s) and PK timepoints may be reconsidered and amended 
during the study based on the emerging safety and pharmacokinetic data. 
3.1. Dose Levels to Be Tested
The possible dose levels for Arms A, B, and C are shown in Table 7.  For Arms A and B, 
dose levels differ only in the dose of PF-05212384.  For Arm C, dose levels differ for 
PF-05212384 and dacomitinib. 
During the dose-escalation portion, patients who have not experienced DLT at the lower 
doses will be treated at the next cohort which has been cleared for safety (the dose level has 
not been determined to exceed the MTD).  The decision regarding the implementation of 
intra-patient dose escalation in patients treated at the MTD expansion will be considered 
once the MTD has been identified.  
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Table 7.
Dose Levels for Arms A, B and C
Arm A
Dose Level
PF-05212384 mg/wk
IV
Docetaxel mg/m2 IV q 3 wks
A(-1)
75
75
A1#
90
75
A2
110
75
A3
130
75
A4
150
75
A5
180
75
A6*
215
75
A7*
260
75
A8*
310
75
#  Starting dose level.
* April 1, 2015, Pfizer Inc. decided to stop enrollment in Arm A.
Arm B
Dose Level
PF-05212384 mg/wk
IV
Cisplatin mg/mg2 IV q 3wks
B(-1)
75
75
B1#
90
75
B2
110
75
B3
130
75
B4
150
75
B5
180
75
B6
215
75
B7
260
75
B8
310
75
#  Starting dose level.
Arm C
Dose Level
PF-05212384 mg/wk
IV
Dacomitnib PO mg qd
C1#
90
30
C1h
90
45
C2
110
30
C2h†
110
45
C3
130
30
C3h†
130
45
C4
150
30
C5*
180
30
C6*
215
30
C7*
260
30
C8*
310
30
#  Starting dose level.
†  Dose level previously determined to exceed the MTD.
* April 1, 2015, Pfizer Inc. decided to stop enrollment in Arm C.
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3.1.1. Criteria for Dose Assignment
3.1.1.1. Criteria for Dose Assignments for Arms A and B 
In Arms A and B, a modified toxicity probability interval (mTPI) method with adjustment 
based on observed DLT rate will be used to guide the dose assignment. The statistical 
description of the method is provided in Section 9.  The dose assignment recommendations 
of the method are provided in Figure 7.  Patients are enrolled in cohorts of 3 patients.  In the 
first cohort, the starting dose level will be assigned as noted in Table 7.  For any subsequent 
cohort of patients, the recommended dose assignment action will be based on the total 
number of patients with DLTs in the current and prior cohorts treated at the same dose level.  
For example, if a cohort of 3 patients are treated at dose level A1 for the first time and one of 
them experiences a DLT, then the recommended action for the next cohort of patients will be 
to stay at the current dose level (S); if this recommendation is accepted, then the selected 
dose level for the next cohort of patients will be A1; if a cohort of 3 additional patients are 
treated at dose level A1 and there are no more DLTs observed, then the cumulative number 
of patients treated at A1 is 6, and the cumulative number of patients with DLTs at A1 is 1, 
thus the recommendation would be to escalate the dose for the subsequent cohort (E).  
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Figure 7.
Recommended Action Based on Cumulative DLT Data at the Current Dose 
Level (Arms A and B)
Cumulative number of patients treated at the current dose level
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cumulative number of patients with DLTs at the current dose level
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
S
E
E
E
E
E
E
E
E
E
E
2
D
D
D
D
D
S
S
S
S
E
E
E
E
E
3
DU
DU
DU
D
D
D
D
S
S
S
S
S
S
4
DU
DU
DU
DU
DU
D
D
D
D
S
S
S
5
DU
DU
DU
DU
DU
DU
D
D
D
D
D
6
DU
DU
DU
DU
DU
DU
DU
DU
D
D
7
DU
DU
DU
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
DU
12
DU
DU
DU
DU
13
DU
DU
DU
14
DU
DU
15
DU
E = Escalate to the next higher dose level
S = Stay at the current dose level
D = De-escalate to the next lower dose level
DU = The current dose level is unacceptably toxic and should be eliminated from further testing
Initially up to 3 patients will be treated in a cohort; occasionally, due to logistical reasons, 
more than 3 but no more than 6 patients may be enrolled in a cohort.  Patients not evaluable 
for assessment of DLT, as described in Section 9.1 may be replaced.  The actual dose level 
selected for the next cohort of patients will take into account the recommended dose level 
from Figure 7 and all available safety data other than DLTs.  Dose-finding for an arm may be 
stopped when one of the following criteria is met:
•
The lowest dose level appears too toxic after at least 3 patients are dosed at that dose 
level.
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•
The maximum sample size in dose finding of 40 evaluable patients per arm has been 
reached.
•
A minimum of 10 evaluable patients have been treated at the estimated MTD. 
DLTs occurring in the first cycle will be used for determining the starting dose in the 
subsequent cohort.  
All significant AEs and SAEs will be reviewed by the Sponsor and the Investigators to 
determine if the dose allocation schedule requires modification.
3.1.1.2. Criteria for Dose Assignment for Arm C
A zone-based design will be employed for Arm C.35 It is a modified 3+3 design that
potentially allows opening of more than one dose level at the same time.  The starting dose 
level is C1.  Dose escalation will proceed according to the sequence in Table 8 until an MTD 
(or two MTDs) is declared, or the Maximum Allowable Dose is reached.  
Table 8.
Dose Escalation Sequence (Arm C)
Arm C
Dacomitinib PO
mg qd
30
45
PF-05212384 mg/wk IV
90
C1#
C1h
110
C2
C2h
130
C3
C3h
150
C4
180
C5*
215
C6*
260
C7*
310
C8*
# Starting dose level.
* April 1, 2015, Pfizer Inc decided to stop enrollment in Arm C.
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As in a classical 3+3 design, dose escalation is indicated if there is no DLT in 3 patients or 
≤1 DLT in 6 patients at the current dose level.  If DLT data at dose level C1 indicates dose 
escalation, then two separate dose escalations from C1 to C2 and from C1 to C1h may occur 
simultaneously (as shown in Table 8).  To open dose level C2h, the DLT data from  the 
preceding two lower dose levels C2 and C1h must both indicate dose escalation, ie, no DLT 
observed in 3 patients or ≤1 DLT in 6 patients for each of them.  
At each dose level, up to 3 patients will be enrolled initially and evaluated for DLT. 
Subsequent dose levels may not be opened until all patients entered at the current dose level 
have been treated and observed for at least one complete cycle and the number of DLTs 
among those patients in their first cycle has been determined.  Patients not evaluable for 
assessment of DLT, as described in Section 9.1, may be replaced.  Dose escalation will 
continue until the Maximum Allowable Dose level is reached or until DLTs are observed in 
at least 2 of the 3-6 patients treated at a dose level, leading to the conclusion that an MTD has 
been exceeded.  The planned cohort size is 3-6 patients per dose cohort however, based upon 
observed toxicity or unexpected clinical findings, individual dose cohorts may be expanded 
beyond 6 patients after discussion and review by the Sponsor’s medical monitor and the 
Investigators.  When a dose level exceeding an MTD has been identified, the next lower dose 
level is declared the MTD if 6 patients have already been treated at that dose level. 
Otherwise 3 additional patients are treated at the next lower dose level, and if zero or 
1 patient experiences DLTs that dose level is declared the MTD.
For Arm C, it is possible that more than one MTD is identified.  In such case, the Sponsor in 
agreement with the Investigators will decide, based on all available data, the most rational 
dose level to enroll additional patients.
3.2. DLT Definition (All Arms)
Severity of adverse events will be graded according to CTCAE version 4.03.  For the purpose 
of dose escalation, any of the following adverse events occurring in the first cycle of 
treatment (starting from the lead-in dose through Cycle 2 Day 1) which are possibly 
attributable to the combination will be classified as DLTs:
•
Hematologic:
•
Grade 4 neutropenia lasting >7 days.
•
Febrile neutropenia (defined as neutropenia ≥Grade 3 and a single body 
temperature >38.3°C or a sustained temperature of ≥38°C for more than one 
hour).
•
Grade ≥3 neutropenia with infection.
•
Grade 3 thrombocytopenia with bleeding.
•
Grade 4 thrombocytopenia.
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•
Non-hematologic:
•
Grade ≥2 pneumonitis.
•
Grade ≥3 toxicities, except pneumonitis, and excluding those that have not been 
maximally treated (eg, nausea, vomiting, diarrhea, hyperglycemia, rash, 
mucositis).
•
Persistent, intolerable toxicities which result in the failure to deliver at least 3 of 
the 4 doses of PF-05212384 during the 1st cycle (including the lead-in dose).
•
Arm A and B: Persistent, intolerable toxicities which result in the failure to 
deliver at least 3 of the 4 doses of PF-05212384 during the 1st cycle (including the 
lead-in dose).
•
Arm C: Persistent, intolerable toxicities which result in the failure to deliver at 
least 3 of the 4 doses of PF-05212384 and 75% of dacomitinib during the 1st cycle 
(including the lead-in dose(s)). 
•
Persistent, intolerable toxicities which result in the delay of the start of the second 
cycle by more than 2 weeks relative to the scheduled start.
•
In an asymptomatic patient, Grade 3 mean QTc prolongation (QTc ≥501 msec) 
will first require repeat testing, re-evaluation by a qualified person, and correction 
of reversible causes such as electrolyte abnormalities or hypoxia for confirmation.  
If, after correction of any reversible causes, the Grade 3 QTc prolongation 
persists, then the event should be considered a DLT. 
3.3. MTD Definition
For Arms A and B, the MTD will be estimated based on isotonic regression (refer to 
Section 9 for details) at the end of the study.  Up to a maximum of 15 patients will be treated 
at the MTD during dose finding to define the tolerability and to evaluate clinical activity.
For Arm C, upon identification of the MTD, additional patients up to a maximum of 15 will 
be treated at the MTD to better define the tolerability and to evaluate clinical activity.  
3.4. Safety and Efficacy Expansion in Patients with TNBC
Based on the rationale provided in Section 1.3.5.1, an expansion cohort will open with 
implementation of Protocol Amendment 5 to assess the clinical activity and continued overall 
safety profile of PF-05212384 in combination with cisplatin in patients with TNBC.  The 
design is shown in the Figure 8 below.
Treatment in the expansion portion of the study will continue until progression of disease, 
uncontrollable toxicity, a decision by the patient or Investigator to discontinue treatment, or 
the study is terminated.  Patients experiencing toxicity may be managed with dose 
modification or discontinuation.  If a patient discontinues PF-05212384 or the combination 
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partner (cisplatin) due to toxicity which is specific to either agent, continuation of patient 
treatment within the study with single agent PF-05212384 or cisplatin will be discussed with 
the Sponsor on a case-by-case basis.  
Figure 8.
Amendment 5 Study Design
3.4.1. Dose Rationale
The recommended Phase 2 dose (RP2D) that will be used in the safety and efficacy 
expansion portion of the study is 180 mg PF-05212384 in combination with cisplatin.  The 
determination of this dose was based on all information related to the overall safety profile, 
clinical activity, and Principal Investigator input for those patients treated at the MTD.
A total of 33 patients were enrolled in Arm B at doses ranging from 90–310 mg/week in arm 
(B1–B8).  Two DLTs were first observed at the 310 mg dose level (Grade 3 oral mucositis) 
leading to a dose reduction to 260 mg dose level.  Rapid onset oral mucositis was then 
observed at the 260 mg dose level (not meeting protocol defined DLT criteria).  Therefore, 
the 310 mg and 260 mg levels were deemed unacceptable to move forward due to rapid onset 
oral mucositis. 
Based on safety profile at 310 mg and 260 mg, the dose level selected for additional study in 
10 patients was 215 mg.  In the 10 patients treated at 215 mg, 6 dose reductions (to 180 mg 
and one patient then further reduced to 150 mg) were observed in 5 patients during Cycle 1.  
Five PF-05212384 Cycle 1 dosing visits were missed in 4 patients due to oral mucositis or 
other significant toxicities. 
Based upon this safety profile at the 215 mg dose level, the RP2D was selected as 180 mg IV 
weekly PF-05212384 in combination with cisplatin (75 mg/mg2 IV q 3wks).
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.
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4.1. Inclusion Criteria – Original Protocol through Amendment 4
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the Investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Histological or cytological proven diagnosis of advanced solid tumor.  
2. For patients enrolled in the dose escalation phase, measurable or evaluable disease as 
defined by RECIST version 1.1; for patients in the MTD cohorts, measurable disease
is required.
3. The following patients will be enrolled:
a.
Arm A: Castrate resistant prostate cancer (CRPC), advanced breast cancer (ABC), 
or non-small cell lung cancer (NSCLC) that are candidates to treatment with a 
docetaxel- based combination.
b. Arm B: Urothelial transitional cell cancer (TCC), triple negative breast cancer 
(TNBC), NSCLC or ovarian cancer (OC) that are candidates to treatment with a 
cisplatin- based combination.
c.
Arm C: Her2+ breast cancer (BC) refractory to prior herceptin or lapatinib, Her2+ 
esophago-gastric cancer, head and neck squamous cell cancer (HNSCC), or 
NSCLC that are candidates to treatment with a dacomitinib-based combination. 
4. Availability of archival tumor biopsy specimens, either formalin-fixed 
paraffin-embedded (FFPE) tumor tissue block or unstained slides, for biomarker
analysis. Patients will need to provide a fresh biopsy if archival material is not 
available. Patients enrolled in the MTD cohorts must be willing to provide matched 
fresh tumor biopsies (if clinically feasible) for the pharmacodynamic biomarker 
studies (See Schedule of Activities, Footnote 23).
5. Age ≥18 years. 
6. ECOG Performance Status (PS) must be 0 or 1.  
7. Adequate bone marrow function, including:
a.
Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L.
b. Platelets ≥100,000/mm3 or ≥100 x 109/L.
c.
Hemoglobin ≥9 g/dL (patients may be transfused to maintain eligibility).
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8. Adequate renal function, including:
a.
Arms A and C: Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated 
creatinine clearance ≥50 ml/min as calculated using the method standard for the 
institution.
b. Arm B: Serum creatinine ≤1 x ULN and an estimated creatinine clearance 
≥60 mL/min.
9. Adequate liver function, including:
a.
Arm A: Total serum bilirubin <1.0 x ULN; Aspartate and Alanine 
Aminotransferase (AST & ALT) ≤1.5 x ULN; and Alkaline phosphatase 
≤2.5 x ULN; (≤5 x ULN in presence of bone metastases).
b. Arms B and C: Total serum bilirubin ≤1.5 x ULN; Aspartate and Alanine 
Aminotransferase (AST & ALT) ≤2.5 x ULN; ≤5.0 x ULN in the presence of 
hepatic metastases; and Alkaline phosphatase ≤2.5 x ULN; (≤5 x ULN in 
presence of bone metastases). 
10. Fasting serum glucose ≤126 mg/dL (7.0 mmol/L).
11. Resolved acute effects of any prior therapy to baseline severity or Grade ≤1 CTC AE 
except for AEs not constituting a safety risk by Investigator judgement or alopecia.
12. Negative serum/urine pregnancy test (for females of childbearing potential) at 
screening and baseline (within 72 hours of the lead-in dose).
13. Male and female patients of childbearing potential must agree to use two highly 
effective method of contraception throughout the study and for at least 90 days after 
the last dose of assigned treatment.  A patient is of childbearing potential if, in the 
opinion of the Investigator, he/she is biologically capable of having children and is 
sexually active. 
Female patients who are not of childbearing potential (ie, meet at least one of the 
following criteria):
•
Have undergone a documented hysterectomy and/or bilateral oophorectomy.
•
Have medically confirmed ovarian failure or; 
•
Achieved post-menopausal status, defined as: cessation of regular menses for at 
least 12 consecutive months with no alternative pathological or physiological 
cause; and have a serum FSH level within the laboratory’s reference range for 
postmenopausal females.  
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14. Evidence of a personally signed and dated informed consent document (ICD)
indicating that the patient has been informed of all pertinent aspects of the study.
15. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures. 
4.2. Exclusion Criteria – Original Protocol through Amendment 4
Patients presenting with any of the following will not be included in the study:
1. Patients with known symptomatic brain metastases.  Patients with previously 
diagnosed brain metastases are eligible if they have completed their treatment and 
have recovered from the acute effects of radiation therapy or surgery prior to the start 
of study medication, have discontinued corticosteroid treatment for these metastases 
for at least 4 weeks and are neurologically stable.
2. Chemotherapy, radiotherapy, biologics, or investigational agents within 4 weeks of 
the lead-in dose (6 weeks for mitomycin C or nitrosoureas). Continued use of
luteinizing-hormone-releasing hormone (LHRH) agonists or low dose steroids 
(<12.5 mg/day of oral prednisone or <2 mg/day dexamethasone) is permitted at the 
Investigator’s discretion for patients with castrate-resistant prostate cancer (CRPC).
3. Major surgery within 4 weeks of baseline disease assessments; or not fully recovered 
from any side effects of previous procedures.
4. Minor procedures such as lymph node biopsy, needle biopsy, and/or placement of 
port-a-caths within 1 week of the lead-in dose; or not fully recovered from any side 
effects of previous procedures.
5. Prior therapy: 
a.
>2 prior regimens containing cytotoxic chemotherapy in the metastatic setting.
b. Prior radiation therapy to >25% bone marrow as estimated by the Investigator.
c.
Arms A: Grade 3 or 4 hypersensitivity reaction associated with prior docetaxel or 
discontinuation of prior docetaxel due to adverse events.
d. Arm B: Grade 3 or 4 hypersensitivity reaction associated with prior cisplatin (or 
other platinum containing compounds) or discontinuation of prior cisplatin due to 
adverse events.
e.
Arm C: Discontinuation of prior dacomitinib due to adverse events.
6. Concurrent use or anticipated need for medications that are mainly metabolized by 
UGT1A9 including their administration within 7-days prior to the first dose of study 
treatment (eg, propofol, propanolol, dapagliflozin, darexaban, mycophenolic acid, and 
tapentadol).
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7. Acetaminophen use within 24 hours of first dose of PF-05212384 (see Section 5.4).
8. Current use or anticipated need for food or drugs that are known strong and/or 
moderate CYP3A4 inhibitors, including their administration within 7-days prior to 
the first PF-05212384 dose and during study treatment (ie, strong CYP3A4 inhibitors: 
grapefruit juice or grapefruit/grapefruit related citrus fruits [eg, Seville oranges, 
pomelos], ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, 
clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, 
fosamprenavir nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan; 
moderate CYP3A4 inhibitors: erythromycin, verapamil, atazanavir, delavirdine, 
fluconazole, darunavir, diltiazem, imatinib, tofisopam, ciprofloxacin, cimetadine).
Aprepitant is classified as a moderate CYP3A4 inhibitor, although it’s use is allowed 
if no suitable alternative can be identified. See Section 5.4.1.
9. Arm C: Current use or anticipated need for food or drugs that are metabolized by 
CYP2D6, and of narrow therapeutic index including their administration within 
10-days prior to the first PF-05212384 dose and during study treatment.  See 
Section 5.4.2 and Appendix 8. 
10. Arm C: Current use or anticipated need for proton pump inhibitors and beta blockers.
11. Concurrent administration of herbal preparations.
12. Patients with current or anticipated need for concomitant medications that are known 
to prolong the QT/QTc interval.
13. Active and clinically significant bacterial, fungal or viral infection including 
hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) 
or acquired immunodeficiency syndrome (AIDS)-related illness.  Baseline viral 
assessment is not required in patients with no known infection.
14. Uncontrolled or significant cardiovascular disease:
a.
Known left ventricular ejection fraction (LVEF) <50%.
b. Myocardial infarction within prior 12 months.
c.
Uncontrolled angina in prior 6 months.
d. Congestive heart failure in prior 6 months.
e.
Any history or 2nd or 3rd degree heart block unless with current pacemaker.
f.
History or clinically significant ventricular arrhythmias such as ventricular 
tachycardia, ventricular fibrillation, or Torsades de Pointes or heart rate 
<50/minute on pre-entry electrocardiogram (ECG).
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g. Prolonged QTc interval at pre-entry ECG.  Mean QTc must be ≤450 msec (CTC 
Grade 1) using Fredericia’s correction formula with manual read by Investigator
if required.
•
The ECG may be repeated for evaluation of eligibility after management 
of correctable causes for observed QTc prolongation;
h. Hypertension defined as >150/100 that cannot be controlled despite optimal 
medical therapy.
15. Arm A: Baseline peripheral neuropathy ≥Grade 2.
16. Arms A: Sensitivity to polysorbate 80.
17. History of interstitial pneumonitis.
18. Arm C: Any clinically significant gastrointestinal abnormalities, which may impair 
intake, transit or absorption of the study drug, such as the inability to take oral 
medications in tablet or capsule form and malabsorption syndrome.
19. Pregnant females or breastfeeding females; males and females of childbearing 
potential who are unwilling or unable to use two (2) highly effective methods of 
contraception as outlined in this protocol for the duration of the study and for 90 days 
after last dose of investigational product.
20. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
4 weeks of the lead-in dose and/or during study participation.
21. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the Investigator, would make the patient 
inappropriate for entry into this study.
22. Patients who are investigational site staff members directly involved in the conduct of 
the trial and their family members, site staff members otherwise supervised by the 
Investigator, or patients who are Pfizer employees directly involved in the conduct of 
the trial.
4.3. Inclusion Criteria – Safety and Efficacy Expansion in patients with TNBC
1. Histological or cytological proven diagnosis of triple negative breast cancer.  
•
Arm 1: Patients with TNBC with no prior cytotoxic chemotherapy therapy in the 
metastatic setting;
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•
Arm 2: Patients with TNBC and one or two prior cytotoxic therapies in the 
metastatic setting.
2. Measurable disease as defined by RECIST version 1.1.
3. Availability of archival tumor biopsy specimens, either formalin-fixed 
paraffin-embedded (FFPE) tumor tissue block or unstained slides, for biomarker
analysis. Patients will need to provide a fresh biopsy if archival material is not 
available.  Patients enrolled in the MTD cohorts must be willing to provide matched 
fresh tumor biopsies (if clinically feasible) for the pharmacodynamic biomarker 
studies (See Schedule of Activities, Footnote 23).
4. Age ≥18 years. 
5. ECOG Performance Status (PS) must be 0 or 1.  
6. Adequate bone marrow function, including:
•
Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L;
•
Platelets ≥100,000/mm3 or ≥100 x 109/L;
•
Hemoglobin ≥9 g/dL (patients may be transfused to maintain eligibility).
7. Adequate renal function, including:
•
Serum creatinine ≤1 x ULN and an estimated creatinine clearance ≥60 mL/min.
8. Adequate liver function, including:
•
Total serum bilirubin ≤1.5 x ULN; Aspartate and Alanine Aminotransferase (AST 
& ALT) ≤2.5 x ULN; ≤5.0 x ULN in the presence of hepatic metastases; and 
Alkaline phosphatase ≤2.5 x ULN; (≤5 x ULN in presence of bone metastases). 
9. Fasting serum glucose ≤126 mg/dL (7.0 mmol/L).
10. Resolved acute effects of any prior therapy to baseline severity or Grade ≤1 CTC AE 
except for AEs not constituting a safety risk by Investigator judgement or alopecia.
11. Negative serum/urine pregnancy test (for females of childbearing potential) at 
screening and baseline (within 72 hours of the lead-in dose).
12. Male and female patients of childbearing potential must agree to use two highly 
effective method of contraception throughout the study and for at least 90 days after 
the last dose of assigned treatment.  A patient is of childbearing potential if, in the 
opinion of the Investigator, he/she is biologically capable of having children and is 
sexually active. 
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Female patients who are not of childbearing potential (ie, meet at least one of the 
following criteria):
•
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
•
Have medically confirmed ovarian failure or; 
•
Achieved post-menopausal status, defined as: cessation of regular menses for at 
least 12 consecutive months with no alternative pathological or physiological 
cause; and have a serum FSH level within the laboratory’s reference range for 
postmenopausal females.  
13. Evidence of a personally signed and dated informed consent document (ICD)
indicating that the patient has been informed of all pertinent aspects of the study.
14. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures. 
4.4. Exclusion Criteria – Safety and Efficacy Expansion in patients with TNBC
Patients presenting with any of the following will not be included in the study:
1. Patients with known symptomatic brain metastases.  Patients with previously 
diagnosed brain metastases are eligible if they have completed their treatment and 
have recovered from the acute effects of radiation therapy or surgery prior to the start 
of study medication, have discontinued corticosteroid treatment for these metastases 
for at least 4 weeks and are neurologically stable.  Consultation with the Sponsor is 
required prior to screening of patients with previously diagnosed brain 
metastases.
2. Chemotherapy, radiotherapy, biologics, or investigational agents within 4 weeks of 
the lead-in dose (6 weeks for mitomycin C or nitrosoureas).  
3. Major surgery within 4 weeks of baseline disease assessments; or not fully recovered 
from any side effects of previous procedures.
4. Minor procedures such as lymph node biopsy, needle biopsy, and/or placement of 
port-a-caths within 1 week of the lead-in dose; or not fully recovered from any side 
effects of previous procedures.
5. Patients with bone-only metastatic disease with no measurable soft tissue component.
6. Prior therapy: 
•
Prior platinum (carboplatin or cisplatin) in either the adjuvant or metastatic 
setting;
•
Prior radiation to >25% bone marrow as estimated by the Investigator.
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7. Concurrent use or anticipated need for medications that are mainly metabolized by 
UDP-glucuronosyltransferase 1-9 (UGT1A9) including their administration within 
7-days prior to the first dose of study treatment (eg, propofol, propanolol, 
dapagliflozin, darexaban, mycophenolic acid, and tapentadol).
8. Acetaminophen use within 24 hours of first dose of PF-05212384 (see Section 5.4).
9. Concurrent administration of herbal preparations.
10. Patients with current or anticipated need for concomitant medications that are known 
to prolong the QT/QTc interval.
11. Active and clinically significant bacterial, fungal or viral infection including 
hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) 
or acquired immunodeficiency syndrome (AIDS)-related illness.  Baseline viral 
assessment is not required in patients with no known infection.
12. Uncontrolled or significant cardiovascular disease:
•
Known left ventricular ejection fraction (LVEF) <50%.
•
Myocardial infarction within prior 12 months.
•
Uncontrolled angina in prior 6 months.
•
Congestive heart failure in prior 6 months.
•
Any history or 2nd or 3rd degree heart block unless with current pacemaker.
•
History or clinically significant ventricular arrhythmias such as ventricular 
tachycardia, ventricular fibrillation, or Torsades de Pointes or heart rate 
<50/minute on pre-entry electrocardiogram (ECG).
•
Prolonged QTc interval at pre-entry ECG.  Mean QTc must be ≤450 msec (CTC 
Grade 1) using Fredericia’s correction formula with manual read by Investigator 
if required.
•
The ECG may be repeated for evaluation of eligibility after management of 
correctable causes for observed QTc prolongation;
•
Hypertension defined as >150/100 that cannot be controlled despite optimal 
medical therapy.
13. History of interstitial pneumonitis.
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14. Pregnant females or breastfeeding females; males and females of childbearing 
potential who are unwilling or unable to use two (2) highly effective methods of 
contraception as outlined in this protocol for the duration of the study and for 90 days 
after last dose of investigational product.
15. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
4 weeks of the lead-in dose and/or during study participation.
16. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the Investigator, would make the patient 
inappropriate for entry into this study.
17. Patients who are investigational site staff members directly involved in the conduct of 
the trial and their family members, site staff members otherwise supervised by the 
Investigator, or patients who are Pfizer employees directly involved in the conduct of 
the trial.
4.5. Life Style Guidelines
Patients will be advised to report any reaction to sun exposed skin.  In addition, special 
precautions should be taken to limit any potential photo irritation effect, by minimizing the 
patients’ exposure to light including high intensity UVb sources such as tanning beds, 
tanning booths and sunlamps.  Patients should be encouraged to apply sunscreen/sunblock 
daily.
In this study, patients of childbearing potential will receive PF-05212384, a compound for 
which the teratogenic risk is currently unknown.  Two (2) methods of highly effective 
contraception must be used throughout the study and continued for 90 days after the last 
dose.  The investigator or his/her designee, in consultation with the patient, will select two 
appropriate methods of contraception for the individual patient from the permitted list of 
contraception methods, and instruct the patient in their consistent and correct use.  The 
investigator or his/her designee, at each study visit, will discuss with the patient the need to 
use highly effective contraception consistently and correctly and document such conversation 
in the patient chart.  In addition, the investigator or his/her designee will instruct the patient 
to call immediately if a selected birth control method is discontinued or if pregnancy is 
known or suspected.  
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected or implanted hormonal methods of 
contraception are allowed provided the patient remains on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
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2. Correctly placed copper containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
suppository).
4. Male sterilization with appropriately confirmed absence of sperm in the 
post-vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy.
4.6. Sponsor Qualified Medical Personnel
The contact information for the Sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the Study Manual. 
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study number, 
contact information for the investigational site and contact details for a help desk in the event 
that the investigational site staff cannot be reached to provide advice on a medical question 
or problem originating from another healthcare professional not involved in the patients 
participation in the study.  The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used in 
the event that the established communication pathways between the investigational site and 
the study team are not available.  It is therefore intended to augment, but not replace the 
established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The help desk 
number is not intended for use by the patient directly and if a patient calls that number they 
will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
5.1.1. Dose Escalation Portion of B2151002
Following full assessment and determination that the patient meets all eligibility criteria and 
has given written informed consent for study participation, arm and dose level allocation will 
be performed by the Sponsor. The Investigator or designee will enroll the patient according 
to the procedures described in the Study Manual. At the end of the enrollment process, a 
patient identification number will be assigned, which must be used on all Case Report Form 
(CRF) pages and on all trial-related documentation and correspondence referencing that 
patient.  
No patient shall receive study drug until the Investigator or designee has received the 
following information in writing from the Sponsor:
•
Confirmation of the patient’s enrolment; and
•
Specification of the arm for that patient; and 
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•
Specification of the dose level for that patient.
The Sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.
Eligible patients will be enrolled to receive one of the three study drug treatment regimens in 
an open-label, unblinded manner.  The possible dose levels are displayed in Section 3.1.  In 
Arms A and B, a modified toxicity probability interval (mTPI) method with adjustment based 
on observed DLT rate will be used to guide the dose assignment (see Section 3.1.1.1). In 
Arm C, a modified 3+3 design is applied that potentially allows opening of more than one 
dose level at the same time (see Section 3.1.1.2).
Patients experiencing a DLT may be managed with dose modification or discontinuation.  
Laboratory values including complete blood count (CBC) and blood chemistry may be 
obtained within 72 hours of the lead-in dose and Day 1 of every subsequent cycle and 
reviewed to ensure appropriate values for dosing. 
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular patient or affect the order in which patients are enrolled.
5.1.2. Safety and Efficacy Expansion in Patients with TNBC
Following full assessment and determination that the patient meets all eligibility criteria and 
has given written informed consent for study participation, the Investigator or designee will 
request enrollment to a specific arm based on the patient’s prior treatment.  Enrollment to a 
specific arm will be performed by the Sponsor. At the end of the enrollment process, a 
patient identification number will be assigned, which must be used on all CRF pages and on 
all trial-related documentation and correspondence referencing that patient.  
No patient shall receive study drug until the Investigator or designee has received the 
following information in writing from the Sponsor:
•
confirmation of the patient’s enrolment; and
•
specification of the arm for that patient; and 
•
specification of the dose level for that patient.
The Sponsor or designee will inform all sites of enrollment via regular study level 
communication.
Patients experiencing toxicity may be managed with dose modification or discontinuation.  
Laboratory values including CBC and blood chemistry may be obtained within 72 hours of 
Day 1 of every subsequent cycle and reviewed to ensure appropriate values for dosing. 
5.2. Drug Supplies
PF-05212384 and dacomitinib are investigational agents and will be supplied free of charge 
by Pfizer.
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Docetaxel and cisplatin are commercially available and will be supplied by the study center 
(costs will be reimbursed by Pfizer) or by Pfizer.  
Study centers will receive a supply of study medication upon activation.  The clinical site 
pharmacy will prepare the study medication supply that is appropriate for the patient on that 
cycle.  Resupplies will be made during the course of the study based on need.  The study 
monitor should be contacted for any issues related to drug supplies.
5.2.1. Formulation and Packaging
5.2.1.1. PF-05212384
PF-05212384 will be supplied as lyophilized powder for infusion and packaged in vials.  The 
vials will be properly labeled according to local regulatory requirements.  The details on drug 
label and supply will be provided in the Investigational Product (IP) Manual.
5.2.1.2. Docetaxel
Docetaxel is commercially available.  Central supply or locally obtained commercial supplies 
of docetaxel will be used. Docetaxel is supplied in single-dose vials containing a sterile 
solution.
5.2.1.3. Cisplatin
Cisplatin is commercially available.  Central supply or locally obtained commercial supplies 
of cisplatin will be used. Cisplatin is supplied as sterile solution in vials or as a lyophilized 
powder.
5.2.1.4. Dacomitinib
Dacomitinib will be dispensed in bottles to patients for home dosing as 15 mg tablets for oral 
administration. The bottles will be properly labeled according to local regulatory 
requirements.  The details on drug label and supply will be provided in the IP Manual.
5.2.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.  Dose adjustments or discontinuations should be managed 
according to the Dose Modification section below.  However, per the Investigator’s
discretion, other dose adjustments may be discussed with the Sponsor.
Any unused product or waste material should be disposed of in accordance with local 
requirements.
5.2.2.1. PF-05212384
All preparations should take place under aseptic conditions.  A pharmacist or pharmacy 
technician (under the supervision of a pharmacist) will prepare PF-05212384.  Specific 
preparation and dispensing instructions are provided in the IP Manual. 
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PF-05212384 is known to be incompatible with sodium chloride and care should be taken to 
avoid contact with saline during both preparation and IV administration.  
5.2.2.2. Docetaxel
Docetaxel will be stored, prepared and dispensed according to product labeling. 
The total docetaxel dose will be administered on Day 1 of each cycle as a 1-hour infusion.
5.2.2.3. Cisplatin
Cisplatin will be stored, prepared and dispensed according to product labeling.
The total cisplatin dose will be administered on Day 1 of each cycle as a 2-hour infusion.  
After Cycle 2, cisplatin infusion duration can be modified per institution practices. 
5.2.2.4. Dacomitinib
Dacomitinib tablets will be packaged in HDPE bottles, dispensed to patients with adequate 
supply for the visit schedule, eg, the lead-in period (7 days) or an entire treatment cycle 
(21 days).  
Dacomitinib tablets should be stored according to the product label and kept in their original 
containers. 
5.2.3. Administration
5.2.3.1. PF-05212384
PF-05212384 should be administered weekly as described in the Schedule of Activities as an 
IV infusion over approximately 30 minutes and as described in the IP Manual.  The use of an 
infusion pump is the preferred method of administration to ensure accurate delivery of the 
investigational product, but gravity drips are allowed.  No premedication is required. In the 
event of allergic, infusion or hypersensitivity reactions, investigators should institute 
treatment measures according to best medical and nursing practice and the infusion time can 
be extended to a maximum of 60 minutes (See Appendix 9).
DO NOT administer any sodium chloride containing solutions or medications 
concomitantly via the same IV line as PF-05212384. Flush IV lines with 5% Dextrose 
Injection both before and after PF-05212384 administration.  
The possible dose levels for different arms are displayed in Section 3.1.
5.2.3.1.1. Dose Escalation Portion of B2151002
Based on preclinical studies, on Day 1 for Cycles 2 and beyond, patients will receive the 
companion drug (docetaxel, cisplatin or dacomitinib) first followed by PF-05212384.15,16  
The infusion of PF-05212384 should be initiated approximately 30 minutes following the 
completion of the docetaxel or cisplatin infusion (Arms A and B) or immediately following 
the ingestion of the dacomitinib dose (Arm C).
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5.2.3.1.2. Retreatment Criteria
PF-05212384 may only be administered on Day 1 of each cycle if all of the following criteria 
are met based on a blood sample collected within the previous 72 hours:
•
ANC ≥1,500/μL;
•
Platelets count ≥100,000/μL;
•
Non-hematologic toxicities (including diarrhea) have returned to baseline or Grade ≤1 
severity (or, at the investigator discretion, Grade ≤2 if not considered a safety risk for 
the patient).
5.2.3.2. Docetaxel
Docetaxel will be administered intravenously at the starting dose of 75 mg/m2 every 3 weeks.  
The total docetaxel dose will be administered as a 1-hour IV infusion.  The dose of docetaxel 
will be calculated using body surface area (mg/m2).
Docetaxel must be used in compliance with its local prescribing information which should be 
reviewed to ensure that appropriate patients are enrolled in the study.
All patients must receive prophylactic pre-medication in order to reduce the incidence and 
severity of fluid retention and hypersensitivity reactions as per Institution’s practices.  
Suggested pre-medication regimen before each chemotherapy administration consists of oral 
dexamethasone 8 mg bid or equipotent doses of oral prednisone or prednisolone or 
methylprednisolone given for 3 days starting 1 day prior to docetaxel administration. Low 
dose steroids (<12.5 mg/day of oral prednisone or <2 mg/day dexamethasone) are permitted
at the Investigator’s discretion for patients with CRPC.
5.2.3.2.1. Retreatment Criteria
Docetaxel may only be administered on Day 1 of each cycle if all the following criteria are 
met based on a blood sample collected within the previous 72 hours:
•
Absolute neutrophil count (ANC) ≥1,500/mm3.
•
ALT, AST ≤1.5 x ULN and Alkaline phosphatase ≤2.5x ULN.
•
Bilirubin within normal limits (WNL).
5.2.3.3. Cisplatin
Cisplatin will be administered intravenously at the starting dose of 75 mg/m2 every 3 weeks.
The total dose will be administered as a 2-hour IV infusion. The dose of cisplatin will be 
calculated using body surface area (mg/m2).
Cisplatin therapy should be immediately preceded and followed by hydration procedures 
according to the institution’s guidelines and administered with appropriate anti-emetics 
including a 5HT3 antagonist.  
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5.2.3.3.1. Retreatment Criteria
Cisplatin may only be administered on Day 1 of each cycle if all the following criteria are 
met based on a blood sample collected within the previous 72 hours:
•
Absolute neutrophil count (ANC) ≥1,500/mm3.
•
Platelets >75,000/mm3 ALT, AST ≤1.5 x ULN.
•
Serum creatinine ≤1 x ULN and an estimated creatinine clearance ≥60 mL/min.
5.2.3.4. Dacomitinib
Patients will self-administer dacomitinib orally, once daily on a continuous basis.  
Dacominitib will be supplied as 15 mg tablets and will be taken on an empty stomach 
(defined as less than 500 calories within 2 hours before or after intake of study medication) 
and with at least 6 oz (180 mL) of water.  Patients will be instructed to record daily 
administration of the study drugs in a patient diary.  Patients will be instructed to swallow 
study drug tablets whole and not to chew them prior to swallowing.  No tablet should be 
ingested if it is broken, cracked, or otherwise not intact.
Patients should be instructed to take their medication at approximately the same time
(±3 hours) every day.  On days of PK sampling patients will be advised not to take their dose 
on that day, and bring their medication with them to the clinic.  The dose for clinic visit days 
will be administered after a pre-dose PK sample is drawn.
The possible dose levels of dacomitinib are displayed in Section 5.2.7.4.
Patients will be instructed that if they miss a day’s dose, they must not make up the missed 
dose, but simply resume the dosing schedule the following day.  Likewise, patients must be 
instructed that if they vomit at any time after taking a dose, they must not “make it up” with 
an extra dose the same day, but resume dosing the next day as prescribed.  Similar to all 
administered doses, any missed or vomited doses must be indicated in the source documents 
and CRFs.
5.2.4. Medication Errors
Medication errors may result from the administration or consumption of the wrong product, 
by the wrong patient, at the wrong time, or at the wrong dosage strength. Such medication 
errors occurring to a study participant are to be captured on the medication error CRF which 
is a specific version of the adverse event (AE) page and on the serious adverse event (SAE)
form when appropriate. In the event of medication error, the Sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:
•
Medication errors involving patient exposure to the investigational product.
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•
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page and, if applicable, any associated adverse event(s) are captured on an 
adverse event (AE) CRF page.
5.2.5. Recommended Dose Modifications
Every effort should be made to administer study treatment on the planned dose and schedule.
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed.  Patients are to be instructed to notify Investigators at the first occurrence 
of any adverse symptom.
Dose modifications may occur in three ways:
•
Within a cycle: dose interruption/reduction until adequate recovery during a given 
treatment cycle. 
•
Between cycles: next cycle administration may be postponed due to toxicity in the 
previous cycle.
•
In the next cycle: dose reduction based on worst toxicity in the previous cycle. 
5.2.6. Dose Interruptions/Delay
PF-05212384: If PF-05212384 treatment is interrupted, the days when treatment is withheld 
are counted as cycle days and missed doses are skipped.  For Arm C, the day treatment is 
restarted with PF-05212384 will be counted as Day 1 of the next cycle, and the previous 
cycle is extended accordingly.  A treatment delay or interruption of >2 consecutive weeks
due to lack of toleration will result in discontinuation of the patient from the study drug, 
following discussion with the Sponsor. If a patient experiences unacceptable toxicities 
considered to be related only to PF-05212384 and not to the combination drug (cisplatin, 
docetaxel, or dacomitinib), continuation of patient treatment within the study with the 
combination drug (cisplatin, docetaxel, or dacomitinib) as a single agent will be discussed 
with the Sponsor on a case-by-case basis.
Docetaxel: If toxicities persist and docetaxel cannot be re-administered for >2 weeks after the 
expected administration of the subsequent cycle (>35 days from the start of docetaxel in the 
current cycle), the Sponsor should be contacted to discuss treatment continuation.  For Arm 
A, the day treatment is restarted with docetaxel will be counted as Day 1 of the next cycle, 
and the previous cycle is extended accordingly.  If a patient experiences unacceptable 
toxicities considered to be related only to docetaxel and not to PF-05212384, continuation of 
patient treatment within the study with PF-05212384 as a single agent will be discussed with 
the Sponsor on a case-by-case basis.
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Cisplatin: If toxicities persist and cisplatin cannot be re-administered for >2 weeks after the 
expected administration of the subsequent cycle (>35 days from the start of cisplatin in the 
current cycle), the Sponsor should be contacted to discuss treatment continuation. For 
Arm B, the day treatment is restarted with cisplatin will be counted as Day 1 of the next 
cycle, and the previous cycle is extended accordingly.  If a patient experiences unacceptable 
toxicities considered to be related only to cisplatin and not to PF-05212384, continuation of 
patient treatment within the study with PF-05212384 as a single agent will be discussed with 
the Sponsor on a case-by-case basis.
Dacomitinib: If dacomitinib treatment is interrupted, the days when treatment is withheld are 
counted as treatment days and missed doses are skipped. The Sponsor should be contacted to 
discuss study continuation of the patient.  Treatment delay or interruption of >2 consecutive 
weeks due to lack of toleration will result in discontinuation of the patient from the study
drug, following discussion with the Sponsor. If a patient experiences unacceptable toxicities 
considered to be related only to dacomitinib and not to PF-05212384, continuation of patient 
treatment within the study with PF-05212384 as a single agent will be discussed with the 
Sponsor on a case-by-case basis.
In the event of a treatment interruption for reasons other than treatment-related toxicity 
(eg, elective surgery) lasting >2 weeks, treatment resumption will be decided in consultation 
with the Sponsor.
5.2.7. Dose Reductions
Following dose interruption or cycle delay due to toxicity, the study drug dose may need to 
be reduced when treatment is resumed.  Dose reductions may be independent for each drug in 
the combination as suggested by the toxicity profile and the adverse event. After the first 
cycle, dose reductions may be required based on the worst toxicity experienced in the 
previous cycle.  Once a dose has been reduced for a given patient, all subsequent cycles 
should be administered at that dose level, unless further dose reduction is required.  Dose 
re-escalation is not allowed unless discussed with the Sponsor.  In the event of multiple 
toxicities, dose modification should be based on the worst toxicity observed.
Suggested dose reduction criteria are described below for each drug administered in this 
study.  These criteria are provided as guidance only.  Decisions on dose reduction and 
resumption of treatment will be determined according to the judgment of the Investigator.
Arms A and B:  Patients experiencing a toxicity that requires dose reduction of 
PF-05212384, may resume dosing at the next lower dose level of PF-05212384 once 
adequate recovery is achieved.  Chemotherapy (ie, docetaxel and cisplatin) should be
maintained at the starting dose unless a chemotherapy-related toxicity mandates a dose 
reduction. Possible dose levels of PF-05212384 according to study arm are shown in 
Table 9.  Recommended dose reductions for PF-05212384, docetaxel and cisplatin are shown 
in Table 10, Table 11 and Table 12, respectively.
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Arm C: Patients treated at dose level 1 of PF-05212384 experiencing a toxicity that requires 
dose reduction of PF-05212384 should be withdrawn from treatment unless otherwise agreed 
between the Investigator and the Sponsor.  Patients treated at dose level 1of dacomitinib
experiencing a toxicity that requires a dose reduction of dacomitinib may resume dosing at 
the next lower dose level, once adequate recovery is achieved.  Patients treated at subsequent 
dose levels of PF-05212384 or dacomitinib experiencing a toxicity that requires dose 
reduction of PF-05212384 or dacomitinib, will have their dose modified once they have 
adequately recovered from the toxicity.  Possible dose levels of PF-05212384 and 
dacomitinib are shown in Table 9 and Table 13, respectively.  Recommended dose reductions 
for PF-05212384 and dacomitinib are shown in Table 10 and Table 14, respectively.
If a patient has a dose reduction for a drug-related toxicity, the dose will not be re-escalated.  
5.2.7.1. PF-05212384
Possible dose levels of PF-05212384 according to study arm are shown in Table 9.
In Arms A and B, patients treated at dose level 1 of PF-05212384 experiencing a toxicity in 
Cycle 1 that requires dose reduction, will receive a reduced dose of PF-05212384 to 
75 mg/wk for Cycle 2 onwards.  
In Arm C, patients treated at dose level 1 of PF-05212384 experiencing a toxicity during 
Cycle 1 that requires dose reduction of PF-05212384, should be withdrawn from treatment 
unless otherwise agreed between the Investigator and the Sponsor.  
Table 9.
Possible Dose Levels of PF-05212384
PF-05212384 mg/wk
Dose Level
Arms A & B
Arm C
(-1)
75
----
1#
90
90
2
110
110
3
130
130
4
150
150
5
180
180
6
215
215
7
260
260
8
310
310
# starting dose
Guidelines for dose modification of toxicities considered related to PF-05212384 are shown
in Table 10.
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Table 10.
PF-05212384 - Dose Modification Guidelines for Related Toxicities
Worst Toxicity (CTCAE v.4.03) 
PF-05212384
Hematologic toxicities:
•
Grade 4 neutropenia ≥7 days
•
Febrile neutropenia (defined as 
neutropenia  Grade ≥3 and a single 
body temperature >38.3°C or a 
sustained temperature of ≥38°C for 
more than one hour)
•
Neutropenic infection (defined as 
Grade 3 or 4 neutropenia with 
Grade ≥3 infection)
•
Grade 3 thrombocytopenia with 
bleeding
•
Grade 4 thrombocytopenia
•
Withhold dose until toxicity is Grade ≤2, then resume treatment at 
1 lower dose level.
•
If the toxicity reoccurs, withhold dose until toxicity is Grade ≤2, 
and then resume treatment at the next lower dose level or 
discontinue treatment at the discretion of the Investigator.
Non-Hematologic Toxicities
Non-Hematologic toxicities not highlighted below:
•
Grade 1 or Grade 2
•
Continue at same dose level.
•
Grade 3 or 4
•
Withhold dose until toxicity is Grade ≤2, then resume treatment at 
1 lower dose level.
•
If the toxicity reoccurs with Grade 3 or 4 severity, withhold dose 
until toxicity is Grade ≤2, and then resume treatment at the next 
lower dose level or discontinue treatment at the discretion of the 
Investigator.
Gastrointestinal toxicities
•
Grade 1 or Grade 2
•
Continue at same dose level.
•
Grade ≥3 nausea/vomiting despite 
optimal antiemetic treatment
•
Grade ≥3 diarrhea despite optimal 
anti- diarrheal treatment
•
Withhold dose until toxicity is Grade ≤2, then resume treatment at 
1 lower dose level.
•
If the toxicity reoccurs with Grade 3 or Grade 4 severity, despite 
optimal supportive care, withhold dose until toxicity is Grade ≤2 
and then resume treatment at the next lower dose level or 
discontinue treatment at the discretion of the Investigator.
Metabolic toxicities
•
Grade 1
•
Continue at the same dose level.
•
Grade ≥2 hyperglycemia
•
Implement hyperglycemia management as described in
Appendix 5.
•
Grade 4 hyperglycemia despite 
optimal anti-hyperglycemic 
treatment
•
Discontinue treatment.
Skin toxicities
•
Grade 1 and Grade 2
•
Continue at the same dose level.
•
Implement skin rash management as described in Appendix 6.
•
Grade 3 and Grade 4
•
Implement skin rash management as described in Appendix 6 and 
withhold dose until toxicity is Grade ≤1; resume treatment at 
1 lower dose level.
•
If the toxicity reoccurs to Grade 3 or 4 despite dose reduction, 
discontinue treatment.
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Worst Toxicity (CTCAE v.4.03) 
PF-05212384
Pulmonary toxicity (pneumonitis)
•
Grade 1
•
Continue at the same dose level.
•
Grade 2
•
Withhold dose until toxicity is Grade ≤1, then resume treatment at 
1 lower dose level.
•
Grade 3 and 4 
•
Discontinue treatment.
Failure to recover
Failure to recover to Grade ≤1 or 
baseline severity for drug-related 
toxicity (or, at the Investigator’s 
discretion, Grade ≤2 for toxicities not 
considered a safety risk for the patient) 
after delaying the initiation of the next 
cycle by a maximum of 2 weeks
•
Discontinue treatment.
5.2.7.2. Docetaxel
The docetaxel dose may be reduced to 60 mg/m2 for Cycle 2 onwards depending on 
individual tolerability.  The minimum dose acceptable for docetaxel will be 60 mg/m2.  
Guidelines for dose modification of docetaxel are shown in Table 11. For the management 
of docetaxel related toxicities and for retreatment criteria at the start of each cycle, refer to 
the product label.
The use of hematopoietic growth factors (eg, G-CSF) for the treatment of febrile neutropenia
will be permitted for Cycle 1 onwards and to support neutrophil counts for Cycles 2 onwards,
according to local guidelines.  In the absence of local guidelines, the ASCO guidelines 2006
should be followed.37
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Table 11.
Docetaxel - Dose Modification Guidelines for Related Toxicities for a New 
Cycle Based on Worst Toxicity Observed in the Prior Cycle
Worst Toxicity (CTCAE v.4.03) in Prior Cycle
Docetaxel Dose (mg/m2)
Hematologic toxicities (1)
•
Grade 4 neutropenia ≥7 days 
60  
•
Febrile neutropenia 
(defined as neutropenia  Grade ≥3 and a single body 
temperature >38.3°C or a sustained temperature of ≥38°C for more 
than one hour)
60 
•
Neutropenic infection (defined as Grade 3 or 4 neutropenia with 
Grade ≥3 infection) 
60 
Non-Hematologic toxicities
Non-Hematologic toxicities not highlighted below:
Grade 3 
60
Grade 4 
Permanently Discontinue
Gastrointestinal toxicities (1)
•
Persistent Grade ≥3 diarrhea despite maximal antidiarrheal 
therapy
60 
Persistent Grade ≥3 nausea despite maximal medical therapy
60 
Persistent Grade ≥3 vomiting despite maximal antiemetic therapy 
60 
Grade ≥3 stomatitis
60 
Hepatic toxicities
Bilirubin >ULN (1,2)
60 
ALT or AST >1.5 ULN (1,2)
60 
AP >2.5 ULN (1,2)
60 
ALT and/or AST >3.5 ULN concomitant with AP >6-ULN
Permanently Discontinue
Other Docetaxel-specific toxicities
Skin toxicities
Grade 3 skin toxicity (1)
60
Grade 4 skin toxicity
Permanently Discontinue
Neuropathy
Grade 3 peripheral (sensory) neuropathy (1)
60
Grade 4 peripheral neuropathy
Permanently Discontinue
Grade ≥3 peripheral motor neuropathy
Permanently Discontinue
Hypersensitivity reaction
Grade ≥3 hypersensitivity reaction (3)
Permanently Discontinue
1
If symptoms persist with dosage adjusted, docetaxel should be discontinued.
2
If abnormal values recover (ie, bilirubin ≤ULN; AST or ALT ≤1.5xULN; AP ≤2.5xULN) within the 
duration of the cycle + a maximum of 2 weeks, re-treat at 1 dose level reduction.  If abnormal values 
do not recover, discontinue treatment with docetaxel.
3
Severe hypersensitivity reactions consist often in severe hypotension, bronchospasm or generalized 
rash/erythema.
5.2.7.3. Cisplatin
The cisplatin dose may be reduced to 60 mg/m2 (approximately 75% of starting dose) and 
40 mg/m2 (approximately 50% of starting dose) for Cycles 2 onwards depending on 
individual tolerability.  Guidelines for dose modification of cisplatin are shown in Table 12. 
For the management of cisplatin related toxicities and for retreatment criteria at the start of 
each cycle, refer to the product label. 
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The use of hematopoietic growth factors (eg, G-CSF) for the treatment of febrile neutropenia 
will be permitted for Cycle 1 onwards and to support neutrophil counts for Cycles 2 onwards,
according to local guidelines.  In the absence of local guidelines, the ASCO guidelines 2006 
should be followed.37
Table 12.
Cisplatin - Dose Modification Guidelines for Related Toxicities for a New 
Cycle Based on Worst Toxicity Observed in Prior Cycle
Worst Toxicity  (CTCAE v.4.03) in Prior Cycle
Cisplatin Dose (mg/m2)
Hematologic toxicities (1)
•
Febrile neutropenia 
(defined as neutropenia ≥Grade 3 and a single body 
temperature >38.3°C or a sustained temperature of 
≥38°C for more than one hour)
60 
•
Grade 4 thrombocytopenia or Grade 3 
thrombocytopenia with bleeding 
60 
Non-Hematologic toxicities
Non-Hematologic toxicities not highlight below:
•
Any Grade 3 toxicity
60 
•
Any Grade 4 toxicity
40 
or discontinue (3)
Gastrointestinal toxicities (1,2)
•
Grade 3 nausea or vomiting despite optimal antiemetic 
prophylaxis and therapy
60 
•
Grade 4 vomiting despite optimal antiemetic 
prophylaxis and therapy
40 
Neurologic toxicities
Peripheral neurotoxicity
•
Grade 2 (1)
40 
or discontinue at Investigator’s discretion
•
Grade 3 (1)
40 when recovered to Grade 2 
or discontinue at Investigator’s discretion  
•
Grade 4
Permanently Discontinue
Ototoxicity (Tinnitus or significant hearing loss)
40 
or discontinue at Investigator’s discretion
Renal toxicities 
Creatinine Clearance (Calculated or Measured)
•
<60 mL/min (1)
40 
•
<45 mL/min
Delay for maximum of 4 weeks. 
If not recovered adequately for re-treatment 
discontinue
(1) If symptoms persist with dosage adjusted, cisplatin should be discontinued.  
(2) Use of antiemetic supportive care is mandatory, as per local practices.
(3) Investigator discretion based on the type of toxicity seen and which course is medically most sound.
5.2.7.4. Dacomitinib
As shown in Table 13, the dacomitinib dose may be reduced for Cycle 2 onwards depending 
on individual tolerability.  The minimum acceptable dose for dacomitinib will be 15 mg QD.  
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Table 13.
Possible Dose Levels for Dacomitinib
Dose Level
Dacomitinib (mg QD PO)
-1
15
1#
30
2
45
# starting dose
Guidelines for dose modification of dacomitinib are shown in Table 14.
Table 14.
Dacomitinib - Dose Modifications Guidelines for Related Toxicities Based on 
Worst Toxicity Observed
Worst Toxicity (CTCAE v.4.03) in Prior 
Cycle
Dacomitinib
Hematologic and Non-Hematologic toxicities
Grade 1 or Grade 2
•
Continue at same dose level. Implement adverse event 
management guidelines as described in Appendix 7.
Grade 3 or intolerable Grade 2
•
Interrupt treatment.
•
Upon recovery to Grade 1 or baseline, resume treatment at 
same dose level or reduce the dose to the next lower dose 
level at the discretion of the Investigator.
Grade 4
•
Interrupt treatment.
•
Upon recovery to Grade 1 or baseline, reduce the dose to 
the next lower dose level or discontinue treatment at the
discretion of the Investigator.
5.2.8. Compliance
5.2.8.1. PF-05212384, Docetaxel, and Cisplatin
The site will complete required dosage Preparation Record located in the study manual.  The 
use of the Preparation Record is preferred but it does not preclude the use of an existing 
appropriate clinical site documentation system.  The existing clinical site's documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose.  This may be used in place of the Preparation Record after 
approval from the Pfizer monitor.
5.2.8.2. Dacomitinib
Patients will maintain diaries to include missed or changed doses, or significantly delayed 
doses (ie, >6 hours from intended dosing time).  Patients will be required to return all unused 
study medication at the beginning of each cycle. The number of tablets returned by the 
patient will be counted, documented and recorded by site personnel.  All empty, partially 
empty and un-used bottles should be returned to the site for drug accountability purposes and 
held at the site until monitored.
The Investigator and study team will also evaluate patient compliance with the study 
regimen. Potential reasons for non-compliant dosing (ie, AEs, lost medication) will be 
followed up by the study site personnel and strategies to improve dosing compliance will be 
explored.
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5.3. Drug Storage and Drug Accountability
The Investigator, or an approved representative (eg, pharmacist), will ensure that all trial 
drug is stored in a secured area, under recommended storage conditions on the product labels, 
and in accordance with applicable regulatory requirements.  Under no circumstances should 
the Investigator or other site personnel supply trial drug to other Investigators, patients, or 
clinics, or allow supplies to be used other than directed by this protocol without prior 
authorization from Pfizer.  Pfizer may supply drug accountability forms that must be used or 
may approve use of standard institution forms (eg, NCI form).  In either case, the forms must 
identify the investigational product, including batch numbers, and account for its disposition 
on a patient by patient basis, including specific dates and quantities.  The forms must be 
signed by the individual who dispensed the drug, and copies must be provided to Pfizer.  
Adequate records documenting receipts, use, return, loss, or other disposition of study drugs 
must be kept.  Study drug (vials and tablets) must be used according to the protocol 
directions.  The reason for missed doses should be entered on the Case Report Form.  To 
ensure adequate records, all trial drug supplies will be accounted for in the case report form 
and drug accountability inventory forms as instructed by Pfizer.  Unless otherwise authorized 
by Pfizer, at the end of the clinical trial all drug supplies unallocated or unused by the 
patients must be returned to Pfizer or its appointed agent (eg, CRO).  If Pfizer authorizes 
destruction at the trial site, the Investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any special 
instructions provided by Pfizer.  Destruction must be adequately documented.
Investigators and site staff are reminded to check temperatures daily (ie, manually or by 
using alarm systems to alert of any excursions) and ensure that thermometers are working 
correctly as required for proper storage of investigational products.  These include 
thermometers for both the room storage and refrigerator storage.  Any temperature 
excursions should be reported to the sponsor. 
The investigational product(s) must be stored as indicated.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the Sponsor.  
Once a deviation is identified, the investigational product must be quarantined and not used 
until the Sponsor provides documentation of permission to use the investigational product.
Storage conditions stated in the SRSD (ie, Investigator Brochure [IB], Core Data Sheet 
[CDS], United States Package Insert [USPI], Summary of Product Characteristics [SPC], or 
Local Product Document [LPD] may be superseded by the label storage. 
5.3.1. PF-05212384
PF-05212384 should be stored as indicated in its original labeled carton, per the labeled 
storage conditions. The product label will supersede any instructions in the IB for 
PF-05212384.  If the investigational product does not appear to be visually appropriate (eg, 
broken vial), it should not be administered and the Sponsor should be contacted immediately 
for further instruction.  
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5.3.2. Docetaxel and Cisplatin
Docetaxel and cisplatin storage conditions are described in the product label for each drug.
5.3.3. Dacomitinib 
Dacomitinib tablets should be stored as indicated, according to the labeled storage conditions
(which may supersede any instructions in the IB for dacomitinib).  Patients should be 
instructed to keep their medication in its original container.
5.4. Concomitant Medication(s)
Palliative and supportive care for disease related symptoms may be administered at the 
Investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines.37 All concomitant medications and blood products, as well as 
interventions (eg, analgesic use, paracentesis, etc) received by patients from screening until 
the End of Treatment visit will be recorded on the CRF.
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted but they 
may be used to treat treatment-emergent neutropenia as indicated by the current ASCO 
guidelines.
Patients currently being treated with bisphosphonates may continue treatment as long as the 
treatment has been initiated before the first dose of study drug.  Initiation of bisphosphonate 
therapy after randomization will be considered progression of disease unless otherwise 
agreed by the Investigator in consultation with the Sponsor. 
Patients on warfarin should be carefully monitored when study drug is initiated and patients 
on study drug should have frequent PT and INR monitoring should anticoagulation with 
warfarin be initiated.
Additionally for over the counter pain or fever management, if no alternative non-steriodal 
anti-inflammatory drugs (NSAIDs) are viable, acetaminophen may be used  but should be 
discontinued 24 hours prior to administration of PF-05212384.  It can be re-initiated 24 hours 
after the end of PF-05212384 infusion.
Patients should avoid concomitant medications that are known to prolong QT/QTc interval.
The docetaxel and cisplatin product labels should be consulted for any restrictions that may 
apply for concomitant medications. 
5.4.1. Drugs Interacting with CYP3A4
In all treatment arms, patients should avoid the use of strong and moderate CYP3A4 
inhibitors as well as strong CYP3A4 inducers.
Because inhibition of CYP3A4 isoenzymes may increase study drug exposure leading to a 
potential increase in toxicities, the use of known strong inhibitors (Strong CYP3A4 
Inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits (eg, Seville oranges, 
pomelos), ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, 
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clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, 
fosamprenavir, nefazodone, lopinavir, troleandomycin, mibefradil, conivaptan; Moderate 
CYP3A4 inhibitors: Erythromycin, verapamil, atazanavir, fluconazole, darunavir, diltiazem, 
delavirdine, imatinib, tofisopam, ciprofloxacin, cimetidine)38 are not permitted from 7-days 
prior to the first dose of study drug until study treatment discontinuation. Aprepitant is 
classified as a moderate CYP3A4 inhibitor, although use is allowed if no suitable alternative 
can be identified.
Study drug metabolism may be induced when taking strong CYP3A4 inducers 
(eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, 
St. John’s Wort) resulting in reduced plasma concentrations.  Therefore co-administration of 
study drug in combination with these and other strong CYP3A4 inducers is not permitted 
from 7-days prior to the first dose of PF-05212384 until study treatment discontinuation.
5.4.2. CYP2D6 Substrates (Arm C only)
Dacomitinib inhibited CYP2D6 activity in vitro with an IC50 of 0.063 μM (~30 ng/mL).  
Drug-drug interaction of dacomitinib with substrates of CYP2D6 could occur depending on 
the systemic concentrations of dacomitinib achieved in the clinical study and dependence of 
the CYP2D6 substrate on 2D6 for metabolism. Therefore drugs dependent on CYP2D6 
metabolism with narrow therapeutic index eg, procainamide, pimozide and thioridazine are 
prohibited in combination with dacomitinib.
The use of drugs that are highly dependent on CYP2D6 for metabolism requires 
consideration of both the therapeutic index and the degree of CYP2D6 metabolism.  
Substitution within the therapeutic class is recommended if possible, otherwise the directions 
below should be followed. 
•
For drugs that are highly dependent on CYP2D6 metabolism: dose reduction should 
be based on substrate sensitivity to CYP2D6 metabolism. As a guidance, a starting 
dose reduction of 75% (25% of the dose given without co-administration with 
dacomitinib) should be considered and close clinical monitoring is required.
•
For drugs that are partly dependent on CYP2D6-mediated metabolism, there is a high 
likelihood of supra-therapeutic exposure in combination with dacomitinib. No dose 
reduction is required when starting dacomitinib, but clinical monitoring is required; 
based on the patient’s response, dose reductions may be necessary.
•
Pro-drugs, or drugs with highly active metabolites such as codeine and tramadol,
should be replaced with an alternative within the therapeutic class as conversion to 
the pharmacologically active moiety is CYP2D6 metabolism-dependent and their 
exposure with the co-administration of dacomitinib may be sub-therapeutic. Opiates 
such as morphine, hydromorphone, oxymorphone and oxycodone can be used as 
substitutes to replace codeine or tramadol for analgesia.
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Appendix 8 provides a comprehensive list of CYP2D6 substrates coded according to the
therapeutic index and the degree of CYP2D6 metabolism. This is not an all inclusive list.  If 
there is uncertainty whether a concomitant medication is contraindicated, the Investigator
should contact the Sponsor study team.
5.4.3. P-glycoprotein Substrates (Arm C only)
Concurrent administration of drugs which are P-glycoprotein (P-gp) substrates and have a 
narrow therapeutic index (eg, digoxin) should be monitored for exaggerated effect and/or 
toxicities.
5.4.4. Strong Amines (Arm C only)
Lidocaine exposures may significantly increase in the presence of strong amines, such as 
dacomitinib. Lidocaine may be used systemically but clinical monitoring (including 
telemetry) is recommended.36
5.4.5. Other Anti-tumor/Anti-cancer or Experimental Drugs
No additional anti-tumor therapy will be permitted while patients are receiving study therapy. 
Additionally, the concurrent use of herbal supplements is not permitted.
Low dose steroids (<12.5 mg/day of oral prednisone or <2 mg/day dexamethasone) or 
luteinizing-hormone-releasing hormone (LHRH) agonists may be used at the Investigator’s 
discretion for patients with CRPC on Arm A.  
5.4.6. Supportive Care 
Palliative radiotherapy is permitted for the treatment of painful bony lesions providing the 
lesions were known to be present at the time of study entry and the Investigator clearly 
indicates that the need for palliative radiotherapy is not indicative of disease progression.  In
view of the current lack of data about the interaction of the investigational agents 
PF-05212384 and dacomitinib with radiotherapy, study drug treatment should be interrupted 
during palliative radiotherapy, stopping 5 days before and resuming treatment after recovery 
of any radiotherapy-related toxicity to baseline. 
Medication intended solely for supportive care (eg, analgesics, antidepressants) may be used 
at the Investigator’s discretion.  
5.4.7. Hematopoietic Growth Factors
The use of hematopoietic growth factors (eg, G-CSF) for the treatment of febrile neutropenia 
will be permitted for Cycle 1 onwards and to support neutrophil counts for Cycles 2 onwards,
according to local guidelines.  In the absence of local guidelines, the ASCO guidelines 2006 
should be followed.37
Erythropoietin may be used at the Investigator’s discretion for the supportive treatment of 
anemia.
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5.4.8. Corticosteroids 
Chronic, systemic high-dose treatment with corticosteroids (prednisone ≥12.5 mg/day or 
dexamethasone ≥2 mg/day) should be avoided with the exception of Arm A.  Treatment with 
docetaxel requires mandatory prophylactic pre-medication with corticosteroids.  Also, low 
dose steroids (<12.5 mg/day of oral prednisone or <2 mg/day dexamethasone) may be used at 
the Investigator’s discretion for patients with CRPC on Arm A.  
Steroids for the acute treatment of skin rash or respiratory toxicity are allowed.
5.4.9. Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and study treatment required to minimize the 
risk of impaired wound healing and bleeding has not been determined.  Stopping study 
treatment is recommended at least 7 days prior to surgery.  Postoperatively, the decision to 
reinitiate study treatment should be based on a clinical assessment of satisfactory wound 
healing and recovery from surgery.
5.4.10. Oral Mucositis – Prophylaxis and Management 
Oral mucositis was observed in 50% of patients treated in the PF-05212384/cisplatin 
combination.  The Sponsor highly recommends one or more of the following strategies for 
prevention of oral mucositis.  These strategies are outlined below and are recommended to 
begin pre-dose on Cycle 1 Day 1 and continued as clinically indicated.
Patients who have not had a dental checkup within 6 months prior to start of dosing are 
encouraged to do so, especially to identify any persistent issue related to recent 
chemotherapy. Once on treatment, patients are to consult the site health care team prior to 
undertaking any dental or oral surgery procedure to determine if it would be appropriate to 
proceed depending on presence of any ongoing oral mucosal inflammation. 
To decrease the rate and severity of oral mucositis, the patient should perform a steroid 
containing “swish-and-spit” regimen eg., dexamethasone 0.5 mg/5 ml swish and expectorate, 
four times daily.  The daily number of steroid containing mouth rinses can be reduced as 
clinically indicated.
Topical anesthetics or systemic analgesics may be used as indicated in judgment of the 
Investigator and according to local clinical practices. 
Patients should practice good oral care including a soft-bristle toothbrush replaced frequently 
and use of bland rinses or moisturizers. Also, frequent sips of water during meals may assist 
swallowing and therefore maintain caloric intake and hydration in patients experiencing oral
pain.
Use of chlorhexidine is to be avoided.
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Between scheduled visits, patient self-report of oral mucosal discomfort or of visible changes 
in appearance to oral mucosa is encouraged. Periodic systematic examination of the oral 
cavity is required at scheduled visits and as otherwise indicated by patient self-report 
between visits.
Consultation with nutritionist is to be considered if toxicity may compromise maintenance of 
adequate caloric intake.
6. STUDY PROCEDURES
All patients being considered for the trial must sign an informed consent for the trial prior to 
any trial specific procedures.  Trial procedures are described in the Section 7 and in the 
Schedule of Activities.  Safety laboratory tests (hematology, blood chemistry, urinalysis, 
coagulation) and tumor assessments may be done up to 72 hours prior to scheduled Day 1 
visit on any cycle to facilitate availability of results to the Investigator at the time of clinic 
visit.
Other tests and/or increased frequency of examinations or clinical follow up may be needed 
for patient management depending on findings emerging from the study.  The results of these 
additional tests or examinations will be recorded on the CRF. 
6.1. Screening
All patients being considered for the trial and eligible for screening must sign an informed 
consent form prior to performing any trial related procedures that are not standard of care.  
The Investigator, or a person designated by the Investigator, will explain the benefits and 
risks of participation in the trial to each patient, patient’s legal representative or impartial 
witness, and obtain written informed consent prior to the patient entering the trial (before 
initiation of non-routine tests and administration of trial drug).
The final ICD must be agreed to by Pfizer and the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) in language readily understood by the patient.  
The Investigator will retain each patient’s original consent form, signed and dated by the 
patient or by the patient’s legal representative, and by the person who conducted the 
informed consent discussion.
This protocol requires clinical visits and evaluations to determine eligibility prior to trial 
enrollment and the first dose of study drug  (See Schedule of activities and its footnotes).  
Required screening and baseline laboratory evaluations are summarized in Section 7.1.3.  
Patients will be assigned individual trial identification numbers at the time they are approved 
and registered for enrollment.
Baseline assessments must be performed within 28 days (unless otherwise specified) prior to 
commencing study treatment, as outlined on the schedule of activities.  Baseline tumor 
biopsy samples may be archival (see Schedule of Activities, Footnote 23) and if the patient 
has consented to a fresh tumor biopsy, this must be performed within 28 days prior to the 
start of study treatment.  Study treatment start is considered 7 days prior to Cycle 1 Day 1 
(Arms A and B) or 14 days prior to Cycle 1 Day 1 (Arm C). 
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As part of the screening/baseline assessment, all patients will undergo a complete medical 
history, including ongoing concomitant medications, clinical assessments (including vital 
signs, height, body weight, ECOG performance status, baseline signs and symptoms, and 
triplicate 12-lead resting ECG), MUGA or ECHO (Arm C patients), and tumor assessments.
Documentation of tumor history (Primary Diagnosis) should include histological or 
cytological classification, stage information, treatment history (surgery, systemic treatment 
and radiotherapy) as well as duration and best response to immediate prior regimen, tumor 
grade, histologic subtype, and relevant tumor-specific molecular markers, if available 
(eg, PI3K/mTOR/Akt pathway alteration [PIK3CA mutation, PTEN loss] KRAS, BRAF, 
HER2 or EGFR gene expression and/or mutation status).  In addition, information regarding 
the sample type for the initial diagnostic biopsy will be collected.
The required baseline laboratory tests include: blood hematology and chemistry, HbA1c, 
pregnancy test (serum or urine), and urinalysis.
Consent will be required for all patients enrolling in this study to access archived tumor 
biopsies to examine variation in proteins and genes associated with PI3K, HER-family 
receptor and MAPK signaling; examples include PTEN and PIK3CA, PIK3R1, AKT, KRAS, 
and BRAF.  If an archived biopsy is not available, a fresh biopsy sample at baseline will be 
required.  Paired tumor biopsies are also required from patients treated in the MTD cohorts
(see Section 7.3).
Following completion of the screening assessments and confirmation of eligibility, patients 
may be enrolled.
For screening procedures see Schedule of Activities and Section 7.
6.2. Study Period
For treatment period procedures, see Schedule of Activities and Section 7.
6.3. Follow-up Visit
For follow-up procedures see Schedule of Activities and Section 7.
6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety or behavioral
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site.  
Reasons for withdrawal of study treatment may include:
•
Objective disease progression according to RECIST;
•
Global deterioration of health status requiring discontinuation;
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•
Adverse event;
•
QTc prolongation of >500 msec or 60 msec over baseline;
•
Pregnancy;
•
Medication error without associated adverse event;
•
Significant protocol violation;
•
Lost to follow-up;
•
Patient no longer willing to participate in study;
•
Study terminated by Sponsor;
•
Death.
Reasons for withdrawal from study follow-up may include:
•
Completed study follow-up;
•
Study terminated by Sponsor;
•
Lost to follow-up;
•
Patient refusal for further follow-up;
•
Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, request the patient to return all unused investigational 
product(s), request the patient to return for a final visit, if applicable, and follow-up with the 
patient regarding any unresolved adverse events.
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
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If the study is prematurely terminated for reasons other than safety, the Sponsor will make 
reasonable efforts, in accordance with applicable local regulatory requirements and laws, to 
provide PF-05212384 and/or dacomitinib to patients deriving therapeutic benefit, for as long 
as appropriate drug supplies are available and, for patients treated in this study, until the 
treatment is authorized and commercially available for this use.  
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator, that may make it unfeasible to 
perform the test. In these cases the Investigator will take all steps necessary to ensure the 
safety and well being of the patient. When a protocol required test cannot be performed the 
Investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible. 
The study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessments
Safety assessments will include collection of AEs, SAEs, vital signs, physical examination, 
ECG (12-lead), left ventricular ejection fraction (LVEF) measurements, and laboratory 
assessments including pregnancy tests.  In addition, the use of concurrent medications will be 
determined.
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed on two occasions prior to starting study 
therapy; once at the start of Screening and once at the baseline visit, within 72 hours of study 
treatment start. A negative pregnancy result is required before the patient may receive the 
investigational product.  Pregnancy tests will also be routinely repeated at every cycle during 
the active treatment period, at the end of study therapy and additionally whenever one 
menstrual cycle is missed or when potential pregnancy is otherwise suspected.  In the case of 
a positive hCG test, the patient will be withdrawn from study medication but may remain in 
the study.  
Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required 
by local regulations.
7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
version 4.03) timing, seriousness, and relatedness.
Baseline signs and symptoms will be recorded at baseline and then reported as adverse events 
during the study if they worsen in severity or increase in frequency.
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7.1.3. Laboratory Safety Assessments
Blood for hematology and chemistry will be drawn prior to the administration of study 
treatment at the time points described in the Schedule of Activities and analyzed at local 
laboratories.
Investigators may have additional blood tests performed for the purpose of planning 
treatment administration, dose modification, or following AEs.
Table 15.
List of Laboratory Test Assessments
Hematology
Chemistry
Urinalysis
Hemoglobin
ALT (SGPT)
BUN or Urea
Urine dipstick for urine protein: If ≥2+ 
protein on urine dipstick, then collect spot 
urine sample to calculate urine protein to 
creatinine ratio.
Platelets
AST (SGOT)
Serum Creatinine
Urine dipstick for urine blood : If positive 
perform a microscopic analysis (Reflex 
Testing)
WBC
Alk Phos
Uric Acid
Absolute 
Neutrophils
Sodium
Glucose (fasted)*
Pregnancy Test
Absolute 
Lymphocytes
Potassium
Insulin
For female patients of childbearing potential,  
serum or urine
Absolute 
Monocytes
Magnesium
HbA1c
Absolute 
Eosinophils
Chloride
Albumin
Coagulation
Absolute 
Basophils
Calcium
Total Protein
INR
Lactate 
dehydrogenase
Phosphorus
PTT
Total Bilirubin
* It is recommended that patients be under fasting conditions (no food or drink within 8 hours) for all blood 
chemistry panels on Day 1 of each cycle.
7.1.4. Vital Signs and Physical Examination
Patients will have a physical exam to include an examination of major body systems and an 
assessment for emergent toxicities or changes from prior visits, weight, vital signs (blood 
pressure and heart rate to be recorded in the sitting position after approximately 5 minutes of 
rest), assessment of ECOG performance status and height; height will be measured at 
baseline only. Complete physical examinations will be conducted by a physician, trained 
physician’s assistant, or nurse practitioner, as acceptable according to local regulation.  
7.1.5. (12-Lead) ECG
Triplicate 12-lead electrocardiogram (ECG) (with a 10-second rhythm strip) tracing will be 
used for all ECGs.  It is preferable that the machine used has a capacity to calculate the 
standard intervals automatically. At each time point (see the Schedule of Activities), three 
consecutive ECGs will be performed at approximately 2 minutes apart to determine the mean 
QTc interval.  If the mean QTc is prolonged (≥501 msec, ie, ≥CTC AE Grade 3), then the 
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ECGs should be re-evaluated by a qualified person at the site for confirmation as soon as the 
finding is made, including verification that the machine reading is accurate. 
If manual reading verifies a QTc of ≥501 msec, immediate correction for reversible causes 
(including electrolyte abnormalities, hypoxia and concomitant medications for drugs with the 
potential to prolong the QTc interval) should be performed.
In addition, repeat ECGs should be immediately performed hourly for at least 3 hours until 
the QTc interval falls below 501 msec. If QTc interval reverts to less than 501 msec, and in 
the judgment of Investigator(s) and Sponsor is determined to be due to cause(s) other than 
study drug, treatment may be continued with regular ECG monitoring. If QTc interval 
>500 msec or an increase of >60 msec is considered to be related to study therapy, the patient 
will be discontinued from the study.  
Prior to concluding that an episode of prolongation of the QTc interval is due to study drug, 
thorough consideration should be given to potential precipitating factors (eg, change in 
patient clinical condition, effect of concurrent medication, electrolyte disturbance) and 
possible evaluation by specialist.
If a patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG should be obtained at the time of the event. Also, additional triplicate 
ECGs may be performed as clinically indicated.
When matched with PK sampling, the ECG should be collected prior to the scheduled PK 
draw; the timing of the PK collection over rides the timing for the ECG collection (ie, if a PK 
sample is scheduled at 1 hour post dose and an ECG is scheduled 1 hour post dose, then the 
ECGs should be collected just prior to the 1 hour PK collection, and the PK sample should be 
collected at the nominal time). 
7.1.6. Left Ventricular Ejection Fraction Measurements (Arm C only)
Determination of LVEF by either MUGA scan or ECHO will be measured at baseline, the 
end of Cycle 3, the end of Cycle 6, and then every 6 cycles for Arm C patients only.  The 
same technique should be used throughout for an individual patient. 
If an absolute decrease in LVEF of >20% is noted, by either MUGA or ECHO, then the 
LVEF will be repeated as soon as feasible using the alternate radiologic method (if 
available); if the decrease is verified further, cardiac evaluation will be undertaken per the 
judgment of Investigator.  In the absence of clinical signs and symptoms of left ventricular 
dysfunction or LVEF <40%, treatment may continue if judgment of the Investigator is that 
patient may benefit from ongoing therapy.  Any clinically significant changes will be 
recorded as adverse events and further evaluated as clinically warranted at the discretion of 
the Investigator.  
For any patient discontinuing therapy for signs or symptoms suggestive of left ventricular 
dysfunction, continued evaluation of LVEF at about 3-4 month interval to assess for 
resolution is recommended.
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7.2. Pharmacokinetics Assessments
Blood samples (3 mL whole blood per sample collection timepoint) will be collected for PK 
analysis of PF-05212384, docetaxel, and dacomitinib (and the desmethyl metabolite 
PF-05199265) as outlined in the Schedule of Activities.  A blood sample of 6 mL of whole 
blood per sample collection timepoint, will be collected for the PK analysis of cisplatin as 
outlined in the Schedule of Activities.  Blood samples for PK assessment will be collected up 
through Cycle 6. PK sampling schedule may be modified based on emerging PK data.  
In addition to samples collected at the scheduled times, when feasible, an additional blood 
sample should be collected from patients experiencing unexpected and/or serious AEs which 
are suspected to be related to study drug treatment and the date and time documented in the 
CRF.
All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing.  However, samples obtained within 10% of the nominal time (eg, within 
6 minutes of a 60 minute sample) will be considered protocol compliant, and the exact time 
of the sample collection noted on the CRF.  If a scheduled blood sample collection cannot be 
completed for any reason, the missed sample time may be re-scheduled with agreement of 
clinical Investigators, patient, and Sponsor.
PK samples will be assayed for PF-05212384, docetaxel, cisplatin and dacomitinib (and its 
metabolite PF-05199265) using validated analytical methods in compliance with Pfizer 
standard operating procedures.  Details regarding the collection, processing, storage and 
shipping of the blood samples will be provided in the Study Manual.  
As part of understanding the pharmacokinetics of the study drugs, samples may be used for 
future metabolite identification and/or further evaluation of the bioanalytical methods.  These 
data will be used for internal exploratory purposes and will not be included in the clinical 
report. Samples collected for this purpose will be retained in accordance to local regulations 
and if not processed during the course of these experiments, will be discarded.
7.2.1. Pharmacokinetic Assessments in the Safety and Efficacy Expansion in TNBC
Blood samples (3 mL whole blood per sample collection timepoint) will be collected for PK 
analysis of PF-05212384 as outlined in the Schedule of Activities.  Blood samples for PK 
assessment will be collected up through Cycle 6. PK sampling schedule may be modified 
based on emerging PK data.  
In addition to samples collected at the scheduled times, when feasible, an additional blood 
sample should be collected from patients experiencing unexpected and/or serious AEs which 
are suspected to be related to study drug treatment and the date and time documented in the 
CRF.
All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing.  However, samples obtained within 10% of the nominal time (eg, within 
6 minutes of a 60 minute sample) will be considered protocol compliant, and the exact time 
of the sample collection noted on the CRF.  If a scheduled blood sample collection cannot be 
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completed for any reason, the missed sample time may be re-scheduled with agreement of 
clinical Investigators, patient, and Sponsor.
PK samples will be assayed for PF-05212384 using validated analytical methods in 
compliance with Pfizer standard operating procedures.  Details regarding the collection, 
processing, storage and shipping of the blood samples will be provided in the Laboratory
Manual.  
As part of understanding the pharmacokinetics of the study drugs, samples may be used for 
future metabolite identification and/or further evaluation of the bioanalytical methods.  These 
data will be used for internal exploratory purposes and will not be included in the clinical 
report. Samples collected for this purpose will be retained in accordance to local regulations 
and if not processed during the course of these experiments, will be discarded.
7.3. Pharmacodynamic Assessments
 
Biomarker assessments are described below in more detail, however additional markers may 
be included as pre-clinical studies or literature reports further elucidate the mechanism of 
action of any of the investigational products.  Details on preparation and handling of all 
biomarker samples including processing, storage, and shipment will be provided in the 
Laboratory Manual.  The source of the samples is listed below in Table 16.  Please also refer 
to the Schedule of Activities and the Laboratory Manual for details pertaining to specific 
days of sample collection and sample preparation.
&&,
&&,
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7.3.1. Tumor Biopsy
Acquisition of the mandatory archival FFPE tumor tissue block or unstained slides 
representing primary or metastatic tumor tissue are required and may be completed prior to 
the 28 day screening window, but it is required for patient enrollment.  Note that if archival 
FFPE tumor tissue cannot be provided, a fresh biopsy is required.  Patients may not be 
enrolled into the study without providing either an archived or fresh tumor sample.  For the 
tumor sample, paraffin blocks are preferred, but freshly cut slides will be accepted.  At least 
twenty unstained, 5-micron slides prepared from the paraffin block must be provided.  
Sample will be analyzed for genetic markers indicative of drug sensitivity (eg, PIK3CA, 
BRCA1, other).  
This study is designed to utilize phosphoproteomics techniques to evaluate signaling 
pathways that could be modified in vivo by the drugs used in this study.  The biomarker 
studies will be used to help understand the in vivo mechanism of action of the agents, levels 
of pathway blockade in response to treatment, and potential mechanisms of resistance owing 
to the inherent plasticity in cancer cell signaling pathways.  
To meet this goal, biopsies obtained pre- and post-study treatment (ie, “paired” or “matched” 
fresh tumor biopsies) will be requested from all patients including the dose escalation and the 
MTD cohorts.  The paired tumor core biopsy are mandatory for patients enrolled in the MTD 
cohorts unless the Investigator considers it to pose a safety risk to the patient; in this case, a 
discussion between the Investigator and Sponsor should take place before a final decision is 
made.  Examples of safety risks may include, but are not limited to pulmonary metastases 
deep within the thoracic cavity with high probability of bleeding or lung injury or liver 
metastases located within the liver posing a high risk of bleeding if biopsied. Biopsies 
obtained pre- and post-study treatment will be requested from all patients in the expansion 
portion of the study enrolling patients with TNBC.
Biopsies will be obtained at screening and after drug administration as indicated in the 
Schedule of Activities.  A formalin fixed paraffin block will be prepared and collected from 
each biopsy.  These paired samples will be analyzed predominantly for phosphoprotein 
biomarkers indicative of pathway modulation, or for genetic markers correlated to drug 
sensitivity (eg, emerging KRAS mutation).  Additional markers may be included as 
pre-clinical studies or literature reports further elucidate the mechanisms of action of any of 
the study drugs.  
 
  
Details on preparation handling of these samples including processing, storage, and shipment 
will be provided in the Laboratory Manual.  
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7.3.2. Whole Blood/Plasma Biospecimens
Whole blood biospecimens will be collected pre dose on Cycle 1 Day 1 and Cycle 2 Day 15 
post-dose, but no more than 72 hours later).  Baseline biospecimens will be utilized for 
circulating tumor cell and germline BRCA analysis.  Peripheral blood mononuclear cells 
(PBMCs) or platelets from whole blood will be isolated for analysis of surrogate protein 
markers for drug sensitivity using reverse phase protein array (RPPA) analysis.
 
7.3.3. Effect of PI3K Inhibition on Glucose Metabolism
A PI3K/mTOR inhibitor should disrupt the cellular uptake and metabolism of glucose.  In the 
Phase 1 studies, administration of PF-05212384 resulted in increased levels of circulating 
glucose, insulin, and c-peptide within one week of therapy, as well as increased levels of 
glycosylated hemoglobin (HbA1c) after about one month of therapy.  These observations 
suggest that gedatolisib can block the PI3K/mTOR signaling in humans and that blood based 
biomarkers can be utilized as pharmacodynamics biomarkers.  The current studies will 
therefore employ metabolic biomarkers such as glucose, insulin, c-peptide and HbA1c as 
pharmacodynamics markers for dual PI3K/mTOR inhibition.
7.4. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging must include 
the chest (chest x-ray or high resolution CT) at baseline and at all subsequent cycles in order 
to monitor for pulmonary effects of the study drug PF-05212384 and to monitor target or 
non-target lesions in the chest.  Imaging should include abdomen and pelvis CT or MRI 
scans if disease is being followed in these areas.  A brain CT or MRI scan for patients with 
known or suspected brain metastases and bone scan and/or bone x-rays for patients with 
known or suspected bone metastases are required.
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments.
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, during treatment as specified in the Schedule of Events, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the End of Treatment visit (if 
not done in the previous 6 weeks). Patients who have had a tumor assessment as standard of 
care within 28 days of the lead-in dose but prior to signing the ICD will not need to have a 
re-assessment solely for the purposes of the study, as long as the appropriate data is available 
for entry onto the study CRF.  
Assessment of response will be made using RECIST version 1.1 (Appendix 2). 
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All patients’ files and radiologic images must be available for source verification and for 
potential peer review. 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
7.6. Patient Reported Outcomes in the Safety and Efficacy Expansion in TNBC
Patient reported outcomes of health-related quality of life and breast cancer specific 
disease/treatment related symptoms will be assessed using European Organization for the 
Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC 
QLQ-C30) and the corresponding module for breast cancer (EORTC QLQ-BR23) 
(Appendix 10 and Appendix 11 respectively). Patients will complete each instrument at 
pre-dose on Day 1 and Day 8 of Cycle 1 and 2, on Day 1 of each  subsequent cycle starting 
with Cycle 3 and at the end of treatment visit. Completed questionnaires are always 
considered source document and must be filed accordingly.
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Patients must complete these instruments in clinic (cannot be taken home) and prior to 
having any tests and to any discussion of their progress with the physician or clinic personnel 
at the site. Interviewer administration in clinic may be used under special circumstances 
(eg, patient forgot their glasses or feels too ill). The instruments will be given to the patient 
in the appropriate language for the site.
7.6.1. EORTC QLQ-C30 and EORTC QLQ-BR23
The EORTC QLQ-C30 (Version 3.0) and the QLQ-BR23 module (Appendix 10 and
Appendix 11, respectively) were selected for inclusion in the study as they are responsive to 
clinical status and change over time and are also the two most commonly used patient 
reported measures in breast cancer clinical studies.47 Both self report measures are also 
widely recognized as clinically valid and reliable measures for assessing global QOL, disease 
symptoms, and treatment related symptoms in breast cancer patients.
The EORTC QLQ-C30 (see Appendix 10) consists of 30 questions which are incorporated 
into five multi-item functional domains (physical, role, cognitive, emotional, and social 
domains); a global health status/ global quality of life (QOL) scale; three multi-item 
symptom scales (fatigue, pain, nausea and vomiting scales); and six single items that assess 
additional cancer-related symptoms (dyspnea, appetite loss, sleep disturbance, constipation, 
and diarrhea) and the perceived financial burden of treatment.  The questionnaire employs 
28 4-point Likert scales with responses from “not at all” to “very much” and two 7-point 
Likert scales for global health and overall QOL.48 For functional and global QOL scales, 
higher scores represent a better level of functioning and are converted to a 0 to 100 scale 
using standard scoring algorithm.49 For symptom-oriented scales, a higher score represents 
more severe symptoms.
The EORTC QLQ-BR23 is a 23-item breast cancer-specific companion module to the 
EORTC QLQ-C30 and consists of two functional scales (body image and sexuality); three 
symptom subscales (arm/hand, breast, and systemic side effects) and single items covering 
sexual enjoyment, distress at hair loss, and future perspective.
Both the EORTC QLQ-C30 and the QLQ-BR-23 module require about 15 minutes to 
complete and are available in many languages.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the Investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the Investigator to 
determine the causality of the AE.  The Investigator is required to assess causality.  
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Follow-up by the Investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the Investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as a SAE.  To 
assist in the determination of case seriousness further information may be requested from the 
Investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  Serious adverse events occurring to a patient
after the active reporting period has ended should be reported to the Sponsor if the 
Investigator becomes aware of them; at a minimum, all serious adverse events that the 
Investigator believes have at least a reasonable possibility of being related to investigational 
product are to be reported to the Sponsor.
AEs (serious and non-serious) should be recorded on the CRF from the time the patient has 
taken at least one dose of investigational product through the patient’s last visit.
•
If a patient begins a new anticancer therapy, the AE reporting period for non-serious 
AEs ends at the time the new treatment is started.  Death must be reported if it occurs 
during the SAE reporting period after the last dose of investigational product, 
irrespective of any intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  
•
Abnormal test findings;
•
Clinically significant symptoms and signs;
•
Changes in physical examination findings;
•
Hypersensitivity;
•
Drug abuse;
•
Drug dependency.
Additionally, they may include the signs or symptoms resulting from:
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•
Drug overdose;
•
Drug withdrawal;
•
Drug misuse; 
•
Drug interactions;
•
Extravasation;
•
Exposure during pregnancy (EDP);
•
Exposure via breastfeeding;
•
Medication error;
•
Occupational exposure;
•
Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:
•
Test result is associated with accompanying symptoms; and/or
•
Test result requires additional diagnostic testing or medical/surgical intervention;
and/or
•
Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or
•
Test result is considered to be an AE by the Investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.5. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:
•
Results in death;
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•
Is life-threatening (immediate risk of death);
•
Requires inpatient hospitalization or prolongation of existing hospitalization;
•
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);
•
Results in congenital anomaly/birth defect;
•
Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period. Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE. If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with Common Toxicity Criteria for 
Adverse Events (CTCAE) Grade 5 (see Section on Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.5.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section 8.13.1 SAE Reporting Requirements).
8.5.2. Potential Cases of Drug-Induced Liver Injury 
Liver Function Tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an Investigator deem it necessary to run LFTs because of clinical 
sign/symptom presentation in a patient, such LFT results should be handled and followed up 
as described below.
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events.  
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The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:
•
Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values ≥3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value ≥2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value ≤2 X ULN or not available.
•
For patients with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above.
•
For patients with pre-existing AST or ALT baseline values above the normal range,
AST or ALT value ≥2 times the baseline values and ≥3 X ULN, or ≥8 X ULN 
(whichever is smaller).
•
Concurrent with
•
For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least one time 
the upper limit of normal or if the value reaches ≥3 times the upper limit of 
normal (whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase,
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 
(PT)/international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for LFT abnormalities identified at the time should be considered potential Hy’s 
Law cases irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs.  Such potential Hy’s Law cases should be reported 
as SAEs.
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8.6. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:
•
Rehabilitation facilities;
•
Hospice facilities;
•
Respite care (eg, caregiver relief);
•
Skilled nursing facilities;
•
Nursing homes;
•
Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 
•
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment laboratory abnormality);
•
Social admission (eg, patient has no place to sleep);
•
Administrative admission (eg, for yearly physical examination);
•
Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);
•
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);
•
Hospitalization for observation without a medical AE;
•
Pre-planned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;
•
Admission exclusively for the administration of blood products.
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Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.7. Severity Assessment
GRADE
Clinical Description of Severity
0
No Change from Normal or Reference Range (This grade is not included in the 
Version 4.0 CTCAE document but may be used in certain circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO Adverse Event
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example headache may be severe (interferes significantly with the 
patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.
8.8. Causality Assessment
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the Investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An Investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the Investigator does not know whether or not the investigational product 
caused the event, then the event will be handled as “related to investigational product” for 
reporting purposes, as defined by the Sponsor (see Section on Reporting Requirements).  If 
the Investigator's causality assessment is “unknown but not related to investigational 
product”, this should be clearly documented on study records.  
In addition, if the Investigator determines an SAE is associated with study procedures, the 
Investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
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8.9. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; An example of environmental exposure 
would be a case involving direct contact with a Pfizer product in a pregnant woman 
(eg, a nurse reports that she is pregnant and has been exposed to chemotherapeutic 
products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the Investigator must submit this 
information to the Pfizer Drug Safety Unit on a Serious Adverse Event (SAE) Report Form 
and Exposure in Utero (EIU) Supplemental Form, regardless of whether an SAE has 
occurred.  In addition, the Investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a patient reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EIU Form.  
This must be done irrespective of whether an AE has occurred and within 24 hours of 
awareness of the exposure.  The information submitted should include the anticipated date of 
delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and it’s outcome for
all EIU reports with an unknown outcome.  The Investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow up 
to the initial EIU Form. In the case of a live birth, the structural integrity of the neonate can 
be assessed at the time of birth.  In the event of a termination, the reason(s) for the 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 
•
Spontaneous abortion includes miscarriage and missed abortion;
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•
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the Investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
Investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the Investigator will provide the study patient with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The Investigator must document in the source 
documents that the patient was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.10. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
Investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF, however a copy of the completed SAE Report form 
is maintained in the investigator site file.
8.11. Withdrawal Due to Adverse Events (See also Section Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.13. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.13.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of Investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This timeframe 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
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as well as to the initial and follow-up reporting of exposure during pregnancy, exposure via
breastfeeding and occupational exposure cases.  
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
Investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the Investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an Investigator
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines and/or illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.13.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this trial
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by Pfizer.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Analysis Sets 
1. Safety analysis set.
•
The safety analysis set includes all enrolled patients who receive at least one dose 
of study medication.
2. Full analysis set.
•
The full analysis set includes all enrolled patients.
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3. Per protocol analysis set (evaluable for DLT).
•
The per protocol analysis set includes all enrolled patients who receive at least 
one dose of study medication and who do not have major treatment deviations 
during the first cycle. Patients with major treatment deviations in Cycle 1 are not 
evaluable for DLT and may be replaced. Major deviations include:
•
Administration of less than 75% of the planned Cycle 1 dose of either treatment in 
the combination (provided that the reduction is not due to toxicity attributable to
both agents in the combination).
•
Administration of more than 125% of the planned Cycle 1 dose of either 
treatment in the combination. 
4. PK analysis sets.
•
The PK parameter analysis set is defined as all enrolled patients treated who have 
sufficient information to estimate at least 1 of the PK parameters of interest.
•
Patients with a change to the planned PF-05212384 30 minute infusion time 
(eg, increasing to 60 minutes), will not be included in the summary statistics for 
PK parameters and will be listed separately. 
5. Biomarker Analysis sets
•
Molecular profiling tumor analysis set: is defined as all enrolled patients who start 
treatment and have a baseline archived tumor biopsy FFPE sample (or fresh FFPE 
if archived is not available) successfully analyzed for at least one of the selected 
biomarkers.
•
Expression tumor analysis set: is defined as all enrolled patients who start 
treatment and have both baseline and on-treatment optional fresh FFPE tumor 
biopsy samples successfully analyzed for at least one of the selected biomarkers.
•
Serum PD analysis set: is defined as all enrolled patients who start treatment and 
have a baseline and at least one post-baseline measurement for at least one serum 
PD biomarker.
6. Response Analysis set
•
All enrolled patients who receive at least one dose of study medication, have the 
disease under study, and an adequate baseline tumor assessment.
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9.2. Statistical Methods and Properties
9.2.1. Statistical Methods for Arms A and B
The MTD estimation in Arms A and B employs the mTPI method with adjustment of dose 
assignment criteria based on observed DLT rate.28,34 The mTPI method is a Bayesian 
method with only one assumption about the dose-toxicity relationship, which is, toxicity 
increases as dose increases.  The most important parameter of the mTPI design is the target 
DLT rate at the MTD, which is 25% for this study.  An interval for DLT rate, called 
equivalence interval, is also required for the mTPI method.  Any DLT rate in the equivalence 
interval is considered sufficiently close to the target DLT rate for the purpose of MTD 
estimation.  In this study, the equivalence interval is 20%-32%.  For each dose level, the 
uniform prior is assumed for the DLT rate.  
Dose assignment recommendations are based on the posterior distribution of the DLT rate.  
Specifically, the DLT rate on (0, 1) is divided into three intervals: the equivalence interval, 
the interval below it, and the interval above it.  Unit probability mass (UPM) is calculated for 
each of these intervals based on the posterior distribution of the DLT rate.  The mTPI method 
recommends a higher dose level to the next cohort of patients if the interval below the 
equivalence interval has the highest UPM at the current dose level; and it recommends a 
lower dose level to the next cohort of patients if the interval above the equivalence interval 
has the highest UPM at the current dose level.  To protect patients from highly toxic dose 
levels, a dose level is considered unacceptably toxic and eliminated from further testing, if 
the posterior probability is 95% or higher that its DLT rate is above the target DLT rate, 
provided that 3 or more patients have been treated at the dose level.  In addition, if the total 
number of patients treated at the current dose level is at least 5, then the criteria for 
recommending dose escalation and de-escalation will be adjusted based on the observed DLT 
rate at the current dose level: if it is above 32%, then dose de-escalation will be 
recommended; if it is below 20%, then dose escalation will be recommended, subject to the 
feasibility of the dose so recommended.  The use of observed DLT rate for dose assignment 
is similar to an approach used by the local optimal interval design.34  The dose assignment 
recommendations for cumulative number of patients in the range of 3-15 are presented in 
Figure 7. 
At the end of dose finding, the MTD will be estimated based on isotonic regression.  
Specifically, the MTD estimate will be selected from the dose levels whose isotonic 
estimates of DLT rates are less than or equal to 32%, and it will be the dose level for which 
the isotonic estimate of the DLT rate is closest to the target DLT rate.  If two or more dose 
levels share the same isotonic estimate of DLT rate, the MTD estimate will be the highest 
dose level in the case that the isotonic estimate is lower than the target DLT rate; and the 
lowest dose level in the case that the isotonic estimate is greater than the target DLT rate. 
Simulations of multiple scenarios for the proposed MTD finding method will be described 
and summarized in the Statistical Analysis Plan (SAP).
If 9 or more patients have been treated cumulatively at any dose level and the observed DLT 
rate exceeds 40% among them, then enrollment will be stopped for the affected dose level, 
pending review of the data by the Sponsor and Investigators.
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9.2.2. Statistical Method for Arm C
For Arm C, a zone-based design will be employed for MTD estimation.35  This is a 
3+3 design modified for 2-dimensional MTD finding.  The rule of dose assignment is 
described in Section 3.1.1. 
Table 17 shows the probability of escalating to the next dose level for a range of underlying 
true DLT rates.  For example, for a dose level at which a DLT occurs in 10% of patients, 
there is a greater than 90% probability of escalating.  Conversely, for a dose level at which a 
DLT occurs with a rate of 70%, the probability of escalating is 3%. It is assumed that dose 
escalation occurs with either 0/3 or 1/6 patients experiencing DLTs.
Table 17.
Probability of Escalating Dose Level
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose
level
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001
If the observed DLT rate exceeds 40% among all patients treated at the MTD (including 
those in the dose-escalation cohorts and expansion cohort), then enrollment will be stopped 
for the affected dose level, pending review of the data by the Sponsor and Investigators.
9.2.3. Statistical Method for the Safety and Efficacy Expansion Arm 1 and 2
The expansions will confirm the safety and tolerability of the dose selected as the RP2D 
during the dose escalation while also assessing the anti-tumor activity of PF-05212384 plus 
cisplatin in patients with TNBC.
Enrollment of patients to a specific arm may be discontinued if no or minimal anti-tumor 
activity in that arm is observed during the study.
9.3. Sample Size Determination
On April 1, 2015, Pfizer Inc. decided to stop enrolment in Arms A and C of the B2151002 
clinical trial.  Patients previously identified for enrolment in Arm A and C were permitted to 
enter the study after notification of the decision.  Due to closure, the MTD of those 
combinations will not be established.  All references to objectives, endpoints, study design, 
assessments, etc. and analysis of data in Arm A and C will be limited to the number of 
patients treated up to the enrolment discontinuation date for each Arm (June 10, 2015 for 
Arm A and 06 July 2015 for Arm C).  The decision is based on the company’s change in 
prioritization for the portfolio and is not due to any safety/efficacy concerns or regulatory 
interactions.
There are 3 arms in the dose escalation portion of the study.  For each arm, the primary 
objective is to estimate the MTD.  
For Arms A and B, the dose escalation is with respect to PF-05212384 only.  A total of 
21 patients were enrolled in Arm A and approximately 40 are expected to be enrolled in 
Arm B. The sample size for Arm B will vary depending on the number of DLTs observed.  
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It is expected that approximately 40 patients will be needed, however, due to the number of 
DLTs this may vary. 
For Arm C, there were 2 components prior to the April 1, 2015 decision.  In the first 
component, patients participated in a dose escalation phase aimed at estimating the MTD.  
The study did not proceed to the second component and a total of 33 patients were enrolled.
Sample Size Determination for the Safety and Efficacy Expansion in TNBC
The TNBC expansion portion of the study will enroll 30 response-evaluable patients, 
including 15 in Arm 1 and 2, respectively, to estimate the objective response rate (complete 
response (CR)+partial response (PR)). 
•
For 1st line patients (Arm 1):
•
Posterior Bayesian probabilities will be used to assess the probabilities of 
anti-tumor activity. For example, using a non-informative Jeffrey’s prior, a 
60% response rate (confirmed overall response rate (ORR): CR+PR) (9 out of 
15 patients) would have a posterior probability equal to 88% that the true 
response is not inferior to 45%.
•
For 2nd/3rd-line patients (Arm 2)
•
Posterior Bayesian probabilities will be used to assess the probabilities of 
anti-tumor activity. For example, using a non-informative Jeffrey’s prior, a 
40% response rate (confirmed ORR: CR+PR) (6 out of 15 patients) would have a 
posterior probability equal to 91% that the true response is not inferior to 25%.
The total sample size for the study is approximately 124 patients.
9.4. Efficacy Analysis
9.4.1. Efficacy Analysis for the Dose Escalation 
In the dose escalation portion of the study, anti-tumor activity is a secondary objective.
Tumor response will be presented in the form of patient data listings that include, but are not 
limited to, tumor type, starting dose, tumor response at each visit, and best overall response.  
In addition, dates of progression, death, first response and last tumor assessment will be 
listed.
If the data permits, objective response rate and clinical benefit response rate will be provided 
by arm and by tumor type.  Objective response includes CR and PR.  Clinical benefit 
response includes PR, CR and SD (≥24 weeks from the first dose to treatment failure).
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9.4.2. Efficacy Analysis for the Safety and Efficacy Expansion in TNBC
In the expansion portion of the study, objective response is the primary endpoint.  Objective 
response rate, clinical benefit response rate, duration of response (DOR), and PFS will be
calculated for expansion Arm 1 and 2.  Objective response includes CR and PR.  Clinical 
benefit response (CBR) includes CR, PR and SD (≥24 weeks from first dose to treatment 
failure).
DOR is calculated from first date of PR or CR to the date of progression or death due to any 
cause. In the event of no progression or death, the last tumor assessment date without 
progression will be used in this calculation. 
PFS is defined as the time from first dose to date of first documentation of progression or 
death due to any cause.  Details of censoring for PFS will be provided in the SAP.
The posterior probabilities used to assess the probabilities of anti-tumor activity will be 
calculated based on the final number of responders and response-evaluable patients.
Tumor response will be presented in the form of patient data listings that include, but are not 
limited to, starting dose, tumor response at each visit, and best overall response.  In addition, 
dates of progression, death, first response, and last tumor assessment will be listed.
9.5. Analysis of Other Endpoints
9.5.1. Analysis of Single- and Multiple-Dose Pharmacokinetics
Plasma pharmacokinetic parameters including the maximum plasma concentration (Cmax), 
time to maximum plasma concentration (Tmax), and area under the plasma concentration 
versus time curve (AUClast, AUCτ) for PF-05212384, docetaxel, cisplatin and dacomitinib
will be estimated using non-compartmental analysis.  If data permit or if considered 
appropriate, area under the plasma concentration versus time curve to infinity (AUCinf), 
terminal elimination half-life (t½), plasma clearance (CL), apparent volume of distribution Vd, 
accumulation ratio (Rac) and linearity ratio (Rss) will also be estimated. The single dose and 
steady-state PK parameters will be summarized descriptively by dose, cycle and day.
For PF-05212384, docetaxel, cisplatin and dacomitinib concentrations will be summarized 
descriptively (n, mean, SD, percent coefficient of variation (CV), median, minimum, 
maximum, geometric mean and its associated CV) by dose, cycle, day and nominal time.  
Individual patient and median profiles of the concentration-time data will be plotted by dose, 
cycle and day (single dose and steady-state) using nominal times.  Median profiles will be 
presented on both linear-linear and log-linear scales.
The observed accumulation ratio and the linearity ratio will be summarized descriptively.  
Each will be analyzed after natural log transformation using a one-way analysis of variance 
with a single term for dose.  The means and 90% confidence intervals (CIs) obtained from 
the model will be back-transformed to provide means and 90% CIs for the accumulation and 
linearity ratios for each dose.
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Trough concentrations will be plotted for each dose using a box-whisker plot by cycle and 
day within cycle in order to assess the attainment of steady-state.
9.5.1.1. Metabolite Profiling
Plasma metabolite profiling will be summarized in a separate report and not included in the 
clinical study report (CSR).
9.5.2. Statistical Analysis of Biomarkers
For biopsy samples, summary statistics (eg, the mean and standard deviation, median, CV, 
and minimum/maximum levels of continuous, and frequency and percentages of categorical 
biomarker measures) will be determined at baseline and post-treatment for each arm.  For 
each pair of specimens, the ratio-to-baseline of these same parameters will also be calculated.
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as Wilcoxan rank sum, linear regression, t-test, and analysis of variance 
(ANOVA).  The statistical approach may examine correlations of biomarker results with 
pharmacokinetic parameters and measures of anti-tumor efficacy.  Graphics may be provided 
as appropriate.
9.6. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the safety analysis 
set.
9.6.1. Analysis of Primary Endpoint
Dose Limiting Toxicity (DLT) is the primary endpoint of the dose escalation portion of the 
study.  The occurrence of DLTs observed in the dosing cohorts is used to estimate the MTD 
as described in Section 3.3.  The number of patients with DLTs will be listed by dosing 
cohort as well as by dose level for each arm.  Adverse Events constituting DLTs will be 
listed per dose level by arm.  
9.6.2. Analysis of Secondary Safety Endpoints
9.6.2.1. Adverse Events
Adverse Events (AEs) will be graded by the Investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version # 4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). The focus of AE summaries, 
which will be by arm, will be on Treatment Emergent Adverse Events, those with initial 
onset or increasing in severity after the first dose of study medication.  The number and 
percentage of patients who experienced any AE, serious AE (SAE), treatment related AE, 
and treatment related SAE will be summarized according to worst toxicity grades.  The 
summaries will present AEs both on the entire study period and by cycle (Lead-in, Cycle 1 
and Cycles beyond 1). 
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9.6.2.2. Laboratory Tests Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each lab assay by arm.  The 
analyses will summarize laboratory tests both on the entire study period and by cycle 
(Lead-in, Cycle 1 and Cycles beyond 1). 
For laboratory tests without CTC grade definitions, results will be categorized as normal, 
abnormal or not done. 
9.6.2.3. Electrocardiogram Assessments
The analysis of ECG results will be based on patients in the safety analysis set who have both 
baseline and on-treatment ECG data.  ECG measurements (an average of the triplicate 
measurements) will be used for the statistical analysis and all data presentations.  Any data 
obtained from ECGs repeated for safety reasons after the nominal time-points will not be 
averaged with the preceding triplicates.  Interval measurements from repeated ECGs will be 
included in the outlier analysis (categorical analysis) as individual values obtained at 
unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors (ie, 
Fredericia’s and possibly other factors).  The adequacy of the correction method may be 
assessed graphically (plots of QT and QTc versus RR) and supplementary transformations 
may be considered, as appropriate. Data will be summarized and listed for QT, HR, RR, PR,
QRS, and QTcF by arm, dose, and time.  The most appropriate correction factor will be 
selected and used for the following analyses of central tendency and outliers and used for the 
study conclusions.  Descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum) will be used to summarize the baseline QTc values and changes from 
baseline in QTc by arm, dose, and time point. For each patient and by arm, the maximum 
change from baseline will be calculated as well as the maximum post-baseline value across 
time-points. Categorical analysis of the QTc data will be conducted on maximum change 
from baseline in QTc and maximum post-baseline QTc.  
Shift tables will be provided for baseline vs. worst on treatment QTc using the maximum 
CTC AE Grade. Shift tables will also be provided for ECG abnormality on treatment vs 
baseline (yes, no, not done: (n, %)). The effect of drug concentrations on QTc interval 
changes from baseline will be explored graphically. Additional concentration-QTc analyses 
may be performed.  Data may be pooled with other study results and/or explored further with 
PK/PD models.
9.7. Patient Reported Outcomes
The number and percentage of patients who complete the EORTC QLQ-C30 and QLQ-BR23 
will be summarized in a table, as will the reasons for non-completion of these measures.
The mean change of absolute global QOL scores from baseline (and 95% CI) will be 
calculated. Repeated measures mixed model analyses will also be conducted to estimate 
changes in scores over time. The number and proportion of patients who improved, 
worsened, or remained stable for all of the symptom and functional domains, global QOL, 
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and single items of the QLQ-C30 and the QLQ-BR23 will be summarized in a table. 
Analyses will be performed to determine if the change from baseline scores achieve the 
appropriate minimally important difference (MID) cut-off for the scale being examined.
In addition to the above analyses, an examination of the time to deterioration (TTD) for 
global QOL will be carried out using survival analysis methods.
9.8. Data Safety Monitoring Committee
An external Data Safety Monitoring Committee will not be established for the study. For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team with medical and statistical capabilities to review individual and 
summary data collected in the safety and clinical databases. This will include surveillance 
for SAEs according to regulatory guidelines.
Discussions between the Investigators and the Sponsor regarding AEs and laboratory test 
abnormalities seen at each dose level will occur in an on-going manner at regular 
teleconferences and/or meetings to determine the safety profile and risk/benefit ratio and 
determine if further patient enrollment is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
Investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.
The study site may be subject to review by the Institutional Review Board (IRB)/IEC, and/or 
to quality assurance audits performed by Pfizer, or companies working with or on behalf of 
Pfizer, and/or to inspection by appropriate regulatory authorities.
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Records
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
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The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the Investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital's or the physician’s patient chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the Investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the Investigator
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the Investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
Investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  
The Investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with 
the IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should 
be forwarded to Pfizer.
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The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the Investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996, 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any Sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.
Patient names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
patient.  In case of data transfer, Pfizer will maintain high standards of confidentiality and 
protection of patient personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document used during the informed consent process must be reviewed 
by the Sponsor, approved by both the IRB/IEC and available for inspection.
The Investigator must ensure that each study patient, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.  
The Investigator, or a person designated by the Investigator, will obtain written informed 
consent from each patient or the patient's legal representative before any study-specific 
activity is performed. The Investigator will retain the original of each patient's signed 
consent document.
12.4. Patient Recruitment
Advertisements approved by IEC and Investigator databases may be used as recruitment 
procedures.
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12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.  
In addition, the Investigator will inform Pfizer immediately of any urgent safety measures 
taken by the Investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all other Participating Countries
The End of Trial in all participating countries is defined as the Last Patient Last Visit
(LPLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-05212384 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
Investigator.  After notification, the Investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within a 4 week time period.  As directed by Pfizer, all 
study materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trial 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
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www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate safety and/or efficacy of a Pfizer 
product regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations. 
Primary Completion Date is defined as the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies  at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) to Pfizer at 
least 30 days before they are submitted for publication or otherwise disclosed.  If any patent 
action is required to protect intellectual property rights, Investigator agrees to delay the 
disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the study results themselves) before disclosure.
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If the study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
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16. REFERENCES
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25.
Shi J, Yao D, Liu W, Wang N, Lv H, Zhang G, Ji M, Xu L, He N, Shi B, Hou P.  
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Vinters HV, Gera JF, Cavenee WK, Cloughesy TF, Mannin BD, Baldwin AS, Mischel 
PS.  Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes 
chemotherapy resistance.  Cancer Discovery. 2011;1:524-538.
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Santos O, Kaloustian A, Venkatesan A, Hollander I.  Antitumor efficacy of PKI-587, a 
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Study Group.  JCO 2003; 21:3016-3024.
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SJ,  Readett D,  Thatcher N.  A phase III randomized study of gemcitabine and cisplatin 
with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced 
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Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, 
Patil S, Rolski J, Goksel T, de Marinis O-F, Simms L, Sugarman KP, Gandara D.  
Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed 
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S, Liang J, Letrent S, Millham R, Taylor I, Eckhardt SG, Schellens JHM.  Phase I 
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Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for 
dose-finding trials. Clin. Trials. 2010;7(6):653-663.
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Liu S, Yuan Y.  Optimal interval designs for Phase 1 clinical trials.  Statistics in 
Medicine. 2012.  revised. 
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35.
Huang, X, Biswas, S,  Oki, Y et al: A Parallel Phase I/II Clinical Trial Design for 
Combination Therapies. Biometrics 63, 429–436, June 2007.
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Proarrhythmic Potential for Non-antiarrhythmic Drugs. U.S Department of Health and
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Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the 
use of white blood cell growth factors: an evidence-based clinical practice guideline.
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University of Washington. www.druginteractioninfo.org . Accessed May 2009.
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2010. 36: 1938-1948.
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Hudis CA, Gianni L. Triple-negative breast cancer: An unmet medical need. The 
Oncologist 2011; 16: 1- 11. Doi: 10.1634/theoncologist.2011-S1-01.
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Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ…Winer EP. TBCRC 001: 
randomized phase II study of cetuximab in combination with carboplatin in stage IV 
triple-negative breast cancer. J Clin Oncol 2012. 30: 2615-2623.
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Breast Cancer. Version 2.2016. NCCN.org. Downloaded from 
https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
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Sirohi B, Arnedos M, Popat S, Ashley S, Nerukar A…Smith IE. Platinum-based 
chemotherapy in triple-negative breast cancer. Ann Oncol 2008. doi: 
10.1093/annonc/mdn395 First published online: June 20, 2008.
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Narod SA, Dent RA, Foulkes WD. CCR 20th Anniversary Commentary: triple-negative 
breast cancer in 2015—still in the ballpark. Doi: 10.1158/1078-0432. CCR-14-3122.
45.
Baselga J, Gomez P, Greil R, Braga S, Climent MA…Awada A. Randomized phase II 
study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with 
cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. 
J Clin Oncol 2013; 31: 2586-2592.
46.
Gordon V, Banerji S. Molecular Pathways: PI3K pathway targets in triple-negative 
breast cancer. Clin Cancer Res 2013; 19: 3738-44. 
Doi: 10.1158/1078-0432.CCR-12-0274.
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47.
Krohe et al. Patient-Reported Outcomes in Metastatic Breast Cancer: AReview of 
Industry-Sponsored Clinical Trials. Breast Cancer: Basic and Clinical Research 
2016:10 93–102 doi:10.4137/BCBCR.S39385.
48.
Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international 
clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–376.
49.
Fayers PM, Aaronson NK, Bjordal K et al. EORTC QLQ-C30 Scoring Manual, 3rd
edition. Brussels: European Organisation for Research and Treatment of Cancer 2001.
50.
Uhm JE, Park YH, Yi SY, et al. Treatment outcomes and clinicopathologic 
characteristics of triple-negative breast cancer patients who received 
platinum-containing chemotherapy. Int J Cancer 2009; 124, 1457-1462.
51.
NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 2.2016. 
NCCN.org.
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Appendix 1. Abbreviations
ABC
Advanced Breast Cancer
AE
Adverse Event
AIDS
Aquired Immunodeficiency Syndrome
ALT
Alanine Aminotransferases 
ANC
Absolute Neutrophil Count
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferases 
ATP
Adenose Triphosphate
AUC
Area Under the Curve
AUC inf
Area under the plasma concentration-time profie from time zero to 
infinity
BAD
BCL-2 Associated Cell Death
BC
Breast Cancer
BID
Bis In Die (twice daily)
BRCA
Breast Cancer
BRCA1
Breast Cancer 1
BRCA2
Breast Cancer 2
BSA
Body Surface Area
BP
Blood Pressure
BUN
Blood Urea Nitrogen
Cave
Average plasma/serum concentration
CBC
Complete Blood Count
CBR
Clinical Benefit Rate
CDS
Core Data Sheet
CI
Confidence Interval
CL
Plasma clearance
Cmax
Maximum Observed Concentration
CNS
Central Nervous System
CR
Complete Response
CRF
Case Report Form
CRC
Colorectal Cancer
CRM
Continuous Reassessment Method
CRO
Clinical Research Organization
CRPC
Castrate Resistant Prostate Cancer
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed Tomography
CTA
Clinical Trial Application
CTCAE
Common Terminology Criteria for Adverse Events, version 4.0
Ctrough
Observed concentration at end of dosing interval
CV
Percent Coefficient of Variation
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DAI
Dosage Administration Instructions
DLT
Dose Limiting Toxicity
DOR
Duration of Response
DR
Duration of Response
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
ECHO
Echocardiogram
EGFR
Epidermal Growth Factor Receptor
EORTC 
QLQ-C30
European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire Core-30
EORTC 
QLQ-BR23
European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire Breast Cancer Companion Module
EIU
Exposure In Utero
EMA
European Medicines Agency
EU
European Union
FDA
US Food and Drug Administration
FDAAA
US Food and Drug Administration Amendments Act
FFPE
Formalin Fixed Paraffin Embedded
FIH
First In Human
FOX-O
Forkhead Box O Protein
GBM
Glioblastoma Multiforme
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
H&E
Hematoxylin and eosin
HbA1c
Hemoglobin A1c; Glycosylated hemoglobin
HBV
Hepatitis B
HCV
Hepatitis C
HER
Human Epidermal Growth Factor Receptor
HIV
Human Immunodeficiency Virus
HNSCC
Head and Neck Squamous Cell Carcinoma
HR
Heart rate
HRD
Homologous Recombination Deficiency
IB
Investigator’s Brochure
ICD
Informed Consent Document
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
IUD
Intrauterine Device
IUS
Intrauterine System
IV
Intravenous
&&,
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LFT
Liver Function Test
LHRH
Luteinizing-hormone-releasing hormone
LPD
Local Product Document
LPLV
Last Patient Last Visit
LSLV
Last Subject Last Visit
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
Ms
Milliseconds
MTD
Maximum Tolerated Dose
mTPI
Modified Toxicity Probability Interval
mTOR
Mammalian Target of Rapamycin
MID
Minimally Important Difference
MUGA
Multi-gated Radionucleoide Study
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSAIDs
Non-steriodal anti-inflammatory drugs
NSCLC
Non Small Cell Lung Cancer
OC
Ovarian Cancer
OR
Overall Response
ORR
Overall Response Rate
PARP
Poly (ADP-Ribose) Polymerase
PBMC
Peripheral Blood Mononuclear Cell
PCD
Primary Completion Date
PD
Progressive Disease (when in reference to tumor assessments)
PD
Pharmacodynamic (when in reference to pharmacodynamic 
assessments)
PDK-1
Phosphoinositide-Dependent Kinase-1
PET
Positron Emission Tomography
PFS
Progression Free Survival
PI3K
Phosphoinositide 3-kinase
PI3KCA
Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Alpha
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate
PK
Pharmacokinetic 
PO
Per Os (orally)
P-gp
P-glycoprotein
PR
Partial Response or Progesterone Receptor (depending on context)
PRO
Patient Reported Outcome
PS
Performance Status
PT
Prothrombin Time
PTEN
Phosphatase and Tensin Homolog 
QD
Quaque Die (once daily)
QOL
Quality of Life
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QT
Time between the start of the Q wave and the end of the T wave in the 
heart's electrical cycle
QTc
QT Interval Corrected for Rate
QW
Quaque (once weekly)
RP2D
Recommended Phase 2 Dose
RECIST
Response Evaluation Criteria in Solid Tumors
RPPA
Reverse Phase Protein Array
RTK
Receptor Tyrosine Kinase
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease or Standard Deviation (depending on context)
SGOT
Serum Glutamic-Oxaloacetic Transaminase (AST) 
SGPT
Serum Glutamic-Pyruvic Transaminase (ALT) 
SmPC
Summary of Product Characteristics
SOC
Standard of Care
SRSD
Single Reference Study Document
TCC
Transitional Cell Cancer
TKI
Tyrosine Kinase Inhibitor
Tmax
The Time of the Maximum Observed Concentration
t1/2
Half Life
TNBC
Triple Negative Breast Cancer
TORC1
TOR Complex 1
TORC2
TOR Complex 2
TTD
Time To Deterioration
UGT1A9
UDP-glucuronosyltransferase 1-9
UK
United Kingdom
ULN
Upper Limit of Normal
UPM
Unit Probability Mass
USPI
United States Package Insert
WBC
White Blood Cell
WOCBP
Women of Childbearing Potential
WNL
Within Normal Limits
&&,
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Appendix 2. RECIST (Response Evaluation Criteria In Solid Tumors) Version 1.1 
Guidelines
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247. 
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions
Lesions that can be accurately measured in at least one dimension.
•
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).
•
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray.  
•
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.
•
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable disease
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.
•
Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline.  
•
Previous local treatment: A previously irradiated lesion (or lesion patiented to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites
•
Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.
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•
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
Recording Tumor Assessments 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.  
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 
•
If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.
•
Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION.
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate.  
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Target disease
•
Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease. All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.
•
Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed.  
•
Stable: Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds.  
•
Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm.  
•
Indeterminate. Progression has not been documented, and 
•
one or more target measurable lesions have not been assessed.
•
or assessment methods used were inconsistent with those used at baseline.
•
or one or more target lesions cannot be measured accurately (eg, poorly 
visible unless due to being too small to measure).
•
or one or more target lesions were excised or irradiated and have not 
reappeared or increased.  
Non-target disease
•
CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels. All lymph nodes must be ‘normal’ in size (<10 mm short axis).
•
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 
•
PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.  
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•
Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations
•
If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.
•
If progression determination depends on a lesion with an increase possibly due to
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.  
Appendix 2 Table 1. Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
NewLesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
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If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:
Appendix 2 Table 2. Objective Response Status at each Evaluation for Patients with 
Non-Target Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD
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Appendix 3. National Cancer Institute (NCI) common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (Version 4.03 date June 14, 2010) has been placed in the Study Manual for 
this protocol.  Alternatively, the NCI CTCAE may be reviewed on-line at the following NCI 
website: http://ctep.cancer.gov/reporting/ctc.html
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Appendix 4. Eastern Cooperative Oncology Group Performance Status
Grade
ECOG Performance Status*
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair.
5
Dead.
*As published in Am J Clin Oncol 5:649-655, 1982.
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Appendix 5. Guidelines for Management of Hyperglycemia with PF-05212384
In clinical trials, PF-05212384 has been shown to have metabolic effects including 
hyperglycemia.  The following guidelines are provided in an attempt to briefly inform 
Investigators as to the potential evaluation and treatments to be considered, and to attempt to 
standardize approaches to therapy.  These guidelines are not meant to replace institutional 
practices.
On-study hyperglycemia management
•
Patients with HbA1c ≥5.7%- home monitoring at least QD.
•
Fasting blood glucose (FBG) assessed at every visit.
•
Repeat FBG in 1 week if ≥200 mg/dL.
Fasting Blood Glucose
Management¥
≥160 mg/dL on 2
readings 1 week apart
•
For patients without history of DM
•
Lifestyle modification.
•
Initiate metformin therapy.*
•
If FBG ≥200 mg/dL initiate home monitoring QD.
•
If FBG >200-250 mg/dLafter 2 weeks of metformin:
•
Continue metformin and add sulfonylurea. ¥ **
•
If FBG ≥250 mg/dL after 1 week
•
Add sulfonylurea.**
or
•
Add insulin and titrate to maintain FBG <200 mg/dL.
Targets of treatment
– Fasting/AC glucose: <160 mg/dL
– Random glucose: <200 mg/dL
– Avoid hypoglycemia
•
For patients with history of DM.
•
Titrate current medications to maintain FBG 
<200 mg/dL.
•
Consult with endorcrinologist/primary care physician 
who is following DM.
Symptomatic§ Grade 3
(250-500 mg/dL)
•
IV fluids and consider hospitalization.
•
Consider holding study drug dose until ≤Grade 2 or 
baseline and then restarting at original dose level.
Grade 4
•
IV fluids and consider hospitalization.
•
Consider holding study drug dose until ≤Grade 2 or 
baseline and then restarting at 1 lower dose level.
Grade 4 despite
optimal antihyperglycemic
therapy
•
IV fluids and consider hospitalization.
•
Discontinue treatment.
*
Contraindicated in patients with renal insufficiency.
¥
Discontinue oral anti-hyperglycemics and monitor for hypoglycemia when study drug is interrupted for 
lengthy periods or is discontinued.
**
Short acting agents (eg, repaglinide).
§
Symptoms such as, but not limited to hypotension, severe dehydration, severe metabolic abnormalities 
manifested as ECG changes.
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Appendix 6. Skin Toxicity Management with PF-05212384
In clinical studies, PF-05212384 has been shown to induce skin toxicities including rash and 
pruritis.  The following guidelines are provided in an attempt to briefly inform Investigators 
as to the potential evaluation and treatments to be considered, and to attempt to standardize 
approaches to therapy.  These guidelines are not meant to replace institutional practices.
The following charts may be used as a guide in determining %BSA when assessing the 
severity of rash. [source: O'Sullivan, Susan B., Schmitz, Thomas J. Physical Rehabilitation. 
5th ed. F.A. Davis Company, Philadelphia, 2007. p. 1098, Fig 27.9]
Adult
Adult, obese >80 kg
Anatomic structure Surface area
Anatomic 
structure
Surface 
area
Anterior head
4.5%
Head and neck
2%
Posterior head
4.5%
Anterior torso
25%
Anterior torso
18%
Posterior torso
25%
Posterior torso
18%
Leg, each
20%
Anterior leg, each
9%
Arm, each
5%
Posterior leg, each
9%
Genitalia/perineum 0%
Anterior arm, each
4.5%
Posterior arm, each
4.5%
Genitalia/perineum
1%
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Appendix 6 Table 1. Management of Treatment Related Maculopapular Rash
Grade 1 (<10% of BSA) 
Maintain study drug
Start application of topical hydrocortisone to affected areas, eg:
Alclometasone 0.05% cream to head and neck areas
Mometasone 0.05% cream to body
Weekly reassessment
If worsening or lack of improvement after 2 weeks of treatment, 
add treatment for moderate maculopapular rash
Grade 2 (≥10% but ≤30% of BSA)
Maintain study drug
Start application of topical hydrocortisone to affected areas, eg:
Alclometasone 0.05% cream to the head and neck
Mometasone 0.05% cream to body
Start oral prednisone 0.5mg/kg QD
Weekly reassessment
If worsening or lack of improvement after 1 weeks of treatment, 
add treatment for severe maculopapular rash
Grade 3 (>30% BSA)
Study drug should be held until grade ≤1
Start application of topical treatments to affected areas:
Alclometasone 0.05% cream to the head and neck
Mometasone 0.05% cream to body
Start oral prednisone 0.5mg/kg QD
If skin rash worsens or does not improve with 2 weeks of topical 
or oral treatment, patient should be discontinued from study
If rash is resolved to mild rash, resume study drug with 1 step 
dose reduction
Oral corticosteroids should continue for at least one week after 
resumption of reduced dose of study drug.
Discontinue patient from study treatment if severe or intolerable 
maculopapular rash recurs 
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Appendix 6 Table 2. Management of Treatment Related Pruritus
Grade 1
Maintain study drug
Start topical treatment:
Hypoallergenic moisturizing cream
Antihistaminic creams
Topical triamcinolone 0.1% cream
Weekly reassessment
If worsening or lack of improvement after 2 weeks of treatment, add 
treatment for moderate pruritus
Grade 2
Maintain study drug 
Start topical treatment:
Hypoallergenic moisturizing cream
Antihistaminic creams
Topical triamcinolone 0.1% cream
Start oral treatment:
Antihistaminics or
GABA antagonist (gabapentin or pregabalin)
Weekly reassessment
If worsening or lack of improvement after 2 weeks of treatment, add 
treatment for severe pruritus
Grade 3
Study drug should be held until grade ≤1
Start topical treatment:
Hypoallergenic moisturizing cream
Antihistaminic creams
Topical triamcinolone 0.1% cream
Start oral treatment:
Antihistaminics or
GABA antagonist (gabapentin or pregabalin)
Start Doxepin 50mg BID
Weekly reassessment
If skin reactions do not improve with 2 weeks of symptomatic treatment, 
discontinue patient from study drug.
Resume study drug at a reduced dose if recover to mild pruritus.
Discontinue patient from study treatment if intolerable moderate or severe 
reaction recurs at a reduced dose.
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Appendix 6 Table 3. Management of Treatment Related Dry Skin
Grade 1
Maintain study drug 
Start hypoallergenic moisturizing cream or ointment to the face BID and 
ammonium lactate 12% cream to the body BID
Weekly reassessment
If worsening or lack of improvement after 2 weeks of treatment, add 
treatment for moderate dry skin
Grade 2
Maintain study drugs 
Start hypoallergenic moisturizing cream or ointment to the face BID and 
ammonium lactate 12% cream to the body BID or salicylic acid 6% cream 
(if hyperkeratosic lesions are present) to the body BID
Weekly reassessment
If worsening or lack of improvement after 2 weeks of treatment, add 
treatment severe dry skin
Grade 3
Study drug should be held until recovers to mild dry skin
Start hypoallergenic moisturizing cream or ointment to the face BID and 
ammonium lactate 12% cream to the body BID or salicylic acid 6% cream 
(if hyperkeratosic lesions are present) to the body BID
Start triamcinolone 0.25% cream to eczematous areas bid.
Reassess at least weekly
If dry skin does not improve with 2 weeks of symptomatic treatment, 
discontinue patient from study. 
Resume study drugs at a reduced dose if dry skin recovers to mild dry skin. 
Discontinue patient from study treatment if intolerable moderate or severe 
dry skin recurs at a reduced dose.
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Appendix 7. Dacomitinib Adverse Event Management Guidelines
In all instances, it is recommended that patients be instructed at time of starting drug therapy 
to call the Investigator/Site if no improvement in symptoms has been observed after 24 hours 
of patient taking the recommended/optimal pharmacologic treatment.
Abbreviations:
BSA: Body Surface Area
ADL: Activities of Daily Living. 
•
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc.
•
Self care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications and not bedridden.  (Definitions per CTCAEv4).
GABA: gamma-Aminobutyric Acid
DIARRHEA
•
Patients should be encouraged to drink 8 to 10 large glasses of clear liquids per day 
while on study in order to maintain adequate hydration.
•
General dietary measures to limit impact of diarrhea could include:
•
Stop all lactose-containing products in patients with evidence of lactose 
intolerance;
•
Eat frequent small meals if experiencing increased frequency of stools;
•
Consider low fat regimen enriched with bananas, rice, applesauce, and toast.
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Diarrhea Management Guideline
Grade of Event
Management / Next Dose
Grade 1: increase of <4 stools per day over 
baseline;
Loperamide 4 mg at the first onset of diarrhea and then 2 mg every 
2 hours until the patient is diarrhea-free for at least 12 hours. 
(During the night the patient may take 4mg of loperamide every 
4 hours.)
Fluid intake of at least 2 liters (L) should be maintained to avoid 
dehydration: patients are to drink 8-10 large glasses of clear 
liquids. Consideration for maintenance of electrolyte balance 
would include electrolyte-containing drinks, broth, clear juices. 
Study Treatment: should be continued at same dose.
Grade 2: increase of 4-6 stools per day 
over baseline;
Loperamide as above, or consider use of  diphenoxylate 
hydrochloride and atropine sulfate formula (eg Lomotil®, 
Diarced®, Co-Phenotroope®) at standard doses
Fluid intake of at least 2 L should be maintained to avoid 
dehydration. 
Monitor patient closely and consider intravenous hydration. 
Study Treatment: If not improved to ≤Grade 1 within 24 hrs 
despite use of loperamide, hold treatment until Grade ≤1.  If 
diarrhea of > Grade 1 recurs after initial improvement, consider 
reduction of 1 dose level. 
Grade 3: increase of ≥7 stools per day over 
baseline; or incontinence; or limiting self 
care ADL: or hospitalization indicated
Oral therapy with diphenoxylate hydrochloride and atropine 
sulfate formula, or tincture of opium. 
Fluid intake of at least 2 L should be maintained, intravenously if 
necessary. 
Consider use of octreotide (Sandostatin®) 100-150 microgram (μg) 
subcutaneously twice daily with escalation to 500 μg three times 
daily.
Consider hospitalization if does not improve to Grade 2 within 
24 hours, or in presence of fever, abdominal pain,etc.
Study Treatment: Hold therapy.  Upon resolution to ≤Grade 1, 
resume therapy with consideration of dose reduction 
Grade 4: life-threatening 
Maximal inpatient fluid and nutritional support, antibiotics as 
indicated in judgment of Investigator for fever, leucocytosis, 
marked dehydration, etc.
Study Treatment: Hold until ≤Grade 1. Mandatory dose 
reduction when dosing resumed
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DERMATOLOGIC TOXICITY
Acneiform/ Papulopustular Rash:
Acneiform/ Papulopustular Rash Management 
Guideline
Grade 1:
<10% body surface area (BSA) papules and/or 
pustules (with or without symptoms  of pruritis or 
tenderness)
Topical steroids *
And
Topical antibiotic bid (clindamycin 1 - 2%,
erythromycin 1% - 2%, metronidazole 1%)
Grade 2:
10 to 30% BSA papules and / or pustules (with or 
without symptoms  of pruritis or tenderness), or 
psychosocial impact, or limited instrumental  ADL
Oral antibiotic for at least 4 weeks  
(doxycycline 100 mg BD, minocycline 
100mg bd or oxytetracycline 500 mg BD);
Stop topical antibiotic if being used
And
Topical steroids *
Grade 3:
>30% BSA papules and / or pustules (with or 
without symptoms of pruritis or tenderness); or
•
limiting self-care ADL: or
•
associated with local superinfection with oral 
antibiotics indicated
Oral antibiotic for 4 weeks 
(doxycycline 100 mg BD, minocycline 
100mg bd or oxytetracycline 500 mg BD)
If infection suspected (yellow crusts, purulent 
discharge, painful skin/nares):
switch oral antibiotic to broad spectrum/gram 
negative cover for at least 10 days
consider skin swab for bacterial culture, 
And
Topical steroids (continue)*
Consider dermatology consultation
* Moderate/Low strength steroids such as: 
Triamcinolone acetonide 0.025% 
Desonide 0.05%
Aclometasone 0.05% cream
Fluticasone propionate 0.05% 
For patients intolerant or allergic to tetracycline 
antibiotics, use an antibiotic with Staphloccoccus 
coverage (eg, cephalexin, sulfamethoxazole/ 
trimethoprim)
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Dry Skin/ Xerosis:
Prophylaxis against dry skin would include:
•
Initiation of skin moisturizing cream or ointment regimen upon establishment of 
eligibility (ie prior to first dose).  (avoid skin lotions, as they may contain alcohol).
•
Avoidance of excessive exposure to hot water during showering/bathing.
•
Avoidance of household tasks involving immersion in hot water/ detergent/ solvents.
•
Avoidance of excessive sun exposure/tanning.  Use sunscreen containing zinc oxide 
or titatinium dioxide with SPF at least 30: apply every two hours when exposed to 
sun.
Xerosis/ Dry Skin Management Guideline
Grade 1:
<10% BSA and no
associated erythema or pruritis
Over-the-counter Moisturizing cream or ointment 
to face bid 
AND
Ammonium lactate 12% (or equivalent) cream to 
body bid
Grade 2:
10 to 30% BSA and associated with erythema or 
pruritis; or
limited instrumental  ADL
OTC Moisturizing cream or ointment to face bid; 
AND
Ammonium lactate 12% cream OR salicylic acid 
6% cream to body bid
Grade 3
>30% BSA and associated with pruritis; or
limiting self care ADL
OTC Moisturizing cream or ointment to face bid;  
AND
Ammonium lactate 12% cream OR salicylic acid 
6% cream to body bid 
AND
Topical steroid* to eczematous areas bid
*Moderate/Low strength steroid such as:
Triamcinolone acetonide 0.025% (Aristocort A 
cream) 
Desonide 0.05% (DesOwen cream, lotion) 
Aclometasone 0.05% cream (Allocate cream)
Fluticasone propionate 0.05% 
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Paronychia:
Paronychia Management Guideline
Grade 1
Nail fold edema or erythema; or
disruption of the cuticle
Topical Antibiotics and vinegar soaks *
Grade 2
Localized intervention indicated; or oral intervention 
indicated (eg, antibiotic, antifungal, antiviral); or nail 
fold edema or erythema with pain; or associated with 
discharge or nail plate separation; or limiting 
instrumental ADL
Topical antibiotics and vinegar soaks*
Apply silver nitrate weekly
Grade 3
Surgical intervention,  or IV antibiotics indicated; or 
limiting self care ADL
Topical antibiotics and vinegar soaks*
Apply silver nitrate weekly
Surgical consultation as needed
*Topical antibiotics/ vinegar soaks
Topical antibiotics: Clindamycin 1%, erythromycin 
1%
Vinegar soaks consist of soaking fingers or toes in a 
1:1 solution of white vinegar in water for 
15 minutes every day
± For a video on how to apply silver nitrate, visit: 
http://www.youtube.com/watch?v=HF5oopqheJY
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Pruritis/Itching:
Prophylaxis against dry skin would include:
•
Initiation of skin moisturizing regimen prior to first dose. Non-scented emollient skin 
cream should be used;
•
Avoidance of excessive exposure to hot water during showering/bathing;
•
Avoidance of household tasks involving immersion in hot water/ detergent/ solvents;
•
Avoidance of excessive sun exposure/ tanning.  Use sunscreen containing zinc oxide 
or titatinium dioxide with SPF at least 30: apply every two hours when sun exposure 
is anticipated.
Pruritis Management Guideline
Grade 1:
Mild or localized; or topical intervention indicated
Topical steroid moderate strength 
(eg, Triamcinolone acetonide 0.025% 
Desonide 0.05%
Aclometasone 0.05% cream
Fluticasone propionate 0.05% 
or 
Topical antipruritics (pramoxine 1%, doxepin 5% 
cream) applied twice daily
Grade 2
Intense or widespread, intermittent; skin changes 
from scratching (eg, edema, papulation, excoriations, 
lichenification, oozing/crusts); or oral intervention 
indicated; or limiting instrumental ADL
Topical steroid moderate strength
or 
Topical antipruritics (pramoxine 1%, doxepin 5% 
cream) applied twice daily
AND
Oral antihistamines 
Grade 3:
Intense or widespread,  constant; or limiting self care 
ADL or sleep; or oral corticosteroid or 
immunosuppressive therapy indicated
Oral antihistamines
AND
GABA agonists (gabapentin or pregabalin) or 
Doxepin 
Antihistamines: diphenhydramine 25-50 mg TID; 
hydroxizine 25mg TID; fexofenadine 60mg TID
GABA agonists (adjust if renal impairment): 
Gabapentin 300 mg every 8 hours or Pregabalin 
50-75 mg every 8 hours
Tricyclics: Doxepin 25-50 mg every 8 hours
MUCOSITIS
Patients who have not had a dental check up within 6 months prior to start of dosing are 
encouraged to do so, especially to identify any persistent issue related to recent 
chemotherapy. Once on treatment, patients are to consult the site health care team prior to 
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undertaking any dental or oral surgery procedure to determine if it would be appropriate to 
proceed depending on presence of any ongoing mucosal inflammation/ stomatitis. 
Between scheduled visits, patient self-report of oral mucosal discomfort or of visible changes 
in appearance to oral mucosa is encouraged. Periodic systematic examination of the oral 
cavity is required at scheduled visits and as otherwise indicated by patient self-report 
between visits.
Patients should practice good oral care including a soft-bristle toothbrush replaced frequently 
and use of bland rinses or moisturizers. 
Regular use of warm water non-medicated saline rinse is recommended if stomatitis 
develops. Frequent sips of water during meals may assist swallowing and therefore maintain 
caloric intake and hydration in patients experiencing oral pain 
Use of chlorhexidine is to be avoided.
Topical anesthetics or systemic analgesics may be used as indicated in judgment of the 
Investigator and according to local clinical practices. Topical steroid rinses have been 
reported to be helpful in severe cases (eg dexamethasone 0.5 mg/5 ml swish and expectorate 
four times daily).
Consultation with nutritionist is to be considered if toxicity may compromise maintenance of 
adequate caloric intake.
Keratoconjunctivitis
Keratoconjunctivtis Guideline
Grade 1
Asymptomatic or mild symptoms; intervention not 
indicated
No intervention or dose modification is mandated
Grade 2:
Symptomatic; topical intervention indicated; or 
limiting instrumental ADL
Preservative free artificial tears, ointments, and /or 
other therapies as clinically indicated, with a 
follow-up examination within 2 weeks to include 
slit-lamp and fundoscopic exam as per the 
Investigator judgment.  
Study Treatment: If symptom lasts ≥2 weeks, 
withhold treatment until≤Grade 1 and then reduce 
one dose level.
Grade 3:
Limiting self care ADL
Preservative free artificial tears, ointments, and/or 
other therapies as clinically indicated, with a 
follow-up examination within 2 weeks to include 
slit-lamp and fundoscopic exam as per the 
Investigator judgment.  
Study Treatment: Drug should be withheld until 
recovers to≤Grade 1 and then reduce one dose 
level.
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PULMONARY TOXICITY
In the event of new onset of dyspnea, persistent cough, or other pulmonary symptoms,
treatment with either drug should be stopped until patient can be adequately evaluated for
possible development of drug related interstitial lung disease; dose modification is not
appropriate in this setting. Patients should be counseled throughout treatment to alert
investigator or designated team member immediately if they develop new or worsening
respiratory symptoms. If following discussion between the sponsor and the investigator it is
concluded that a thorough investigation has excluded treatment-induced pulmonary toxicity,
and less than 2 weeks have elapsed off treatment, treatment may resume.
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Appendix 8. CYP2D6 Substrates
For CYP2D6 substrates, prohibited drugs and drugs for which substitution, dose modification 
and/or monitoring is advised are listed below. This listing is not an all inclusive list, and will 
be monitored by Sponsor study team for required updates (addition, deletion) but in all
instances Investigators should review potential for drug-drug interaction for concomitant
medications and take appropriate measures of substitution or dose modification.
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CODE
DRUG
THERAPEUTIC CLASS
CODE
DRUG
THERAPEUTIC CLASS
S
amiflamine
Monoamine Oxidase Inhibitors (MAOIs)
HS
metoprolol
Alpha/Beta Adrenergic Antagonists
HS
amitriptyline
Tricyclics and Tetracyclics
S
mexiletine
Antiarrhythmics
S
aripiprazole
Antipsychotics
S
mianserin
Tricyclics and Tetracyclics
HS
atomoxetine 
Psychostimulants
S
mirtazapine
Tricyclics and Tetracyclics
S
brofaromine
Monoamine Oxidase Inhibitors (MAOIs)
HS
nebivolol
Alpha/Beta Adrenergic Antagonists
S
bufuralol
Alpha/Beta Adrenergic Antagonists
S
nefazodone
Serotonin Modulators
S
carvedilol
Alpha/Beta Adrenergic Antagonists
S
nicergoline
Vasodilators
S
chlorpheniramine
H-1 Receptor Antagonists
S
nortriptyline
Tricyclics and Tetracyclics
S
chlorpromazine
Antipsychotics
S
(S)-ondansetronSerotonin HT3 Receptor Antagonists 
S
citalopram
Serotonin Reuptake Inhibitors (SSRIs)
S
oxycodone
Opioids
S
clomipramine
Tricyclics and Tetracyclics
S
pactimibe
Other Antilipemics
S
clozapine
Antipsychotics
S
paroxetine
Serotonin Reuptake Inhibitors (SSRIs)
PD
codeine
Opioids
S
perhexiline
Vasodilators
S
debrisoquine
Other Antihypertensives
HS
perphenazine
Antipsychotics
HS
desipramine 
Tricyclics and Tetracyclics
S
phenformin
Biguanides
S
dexfenfluramine
Anorexics
P
pimozide
Antipsychotics
HS
dextromethorphan 
Antitussives
HS
prajmaline
Antiarrhythmics
S
dihydrocodeine
Opioids
P
procainamide
Antiarrhythmics
S
donepezil
Anticholinesterase Inhibitors
S
propafenone
Antiarrhythmics
HS
doxepin
Tricyclics and Tetracyclics
S
propranolol
Alpha/Beta Adrenergic Antagonists
S
duloxetine
Ser-Nor Reuptake Inhibitors (SNRIs)
S
ranolazine
Cardiovascular Drugs
S
encainide
Antiarrhythmics
S
repinotan
Serotonin Receptor Agonist
S
fesoterodine
Muscarinic Antagonists
S
risperidone
Antipsychotics
S
flecainide
Antiarrhythmics
S
ritonavir
Protease Inhibitors
S
fluoxetine
Serotonin Reuptake Inhibitors (SSRIs)
S
sabeluzole
CNS Agents
S
fluphenazine
Antipsychotics
S
sparteine
Antiarrhythmics
HS
fluvoxamine
 Serotonin Reuptake Inhibitors (SSRIs)
PD
tamoxifen
Antineoplastic Hormonal
S
gefitinib
Kinase Inhibitors
S
tamsulosin
Alpha/Beta Adrenergic Antagonists
S
haloperidol
Antipsychotics
HS
tetrabenazine
CNS Agents
PD
hydrocodone
Opioids
P
thioridazine
Antipsychotics
S
iloperidone
Antipsychotics
S
timolol
Alpha/Beta Adrenergic Antagonists
S
imipramine
Tricyclics and Tetracyclics
HS
tolterodine
Muscarinic Antagonists
S
lasofoxifene
Estrogen Receptor Modulators
PD
tramadol
Other Analgesics
PD
loratadine
H-1 Receptor Antagonists
HS
traxoprodil
Neuroprotectors
S
maprotiline
Tricyclics and Tetracyclics
S
trazodone
Serotonin Modulators
S
methadone
Opioids
S
trimipramine
Tricyclics and Tetracyclics
S
methamphetamine (MA) 
Recreational Drugs
HS
tropisetron
Serotonin HT3 Receptor Antagonists 
S
3,4-methylenedioxy-MA
Recreational Drugs
S
venlafaxine
Ser-Nor Reuptake Inhibitors (SNRIs)
HS
methoxyphenamine
Beta Adrenoreceptor Agonist
HS
vernakalant
Antiarrhythmics
S
Methylphenidate
Psychostimulants
S
zuclopenthixol
Antipsychotics
S
Metoclopramide
Other Antiemetics
HS
P
PD
S
High likelihood of supratherapeutic exposure in combination with 
dacomitinib; dose-reduction and clinical monitoring IS required, if co-
administration cannot be avoided:  starting dose when 
coadministration with dacomitinib: 25% of original dose 
Narrow therapeutic Index : Prohibited in combination 
with dacomitinib
pro-drug: active ingredient ONLY  or partially upon CYP2D6 metabolism. 
High likelihood of subtherapeutic exposure in combination with 
dacomitinib
High likelihood of supratherapeutic exposure in 
combination with dacomitinib; clinical monitoring is 
required and dose-reduction may be necessary
9/5/2012 v1.0 . Pfizer Inc.
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Appendix 9. Management of Allergic Reactions or Anaphylaxis
In the event of allergic, infusion or hypersensitivity reactions, investigators should institute 
treatment measures according to best medical and nursing practice.
The following treatment guidelines should be employed:
If chills and fever occur, the infusion should be interrupted.  Patients may be treated 
symptomatically and the infusion should be restarted at 50% of the original rate.
NCI-CTCAE Grade 1 allergic, infusion or hypersensitivity reaction 
1. Decrease PF-05212384 infusion rate by 50% and monitor for worsening condition.  If 
the reaction worsens, stop the infusion.  Protocol treatment will be discontinued.
NCI-CTCAE Grade 2 allergic, infustion or hypersensitivity reaction 
1. Stop PF-05212384 infusion.
2. Administer bronchodilators, oxygen, acetaminophen, etc. as medically indicated.
3. Resume infusion at 50% of previous rate once reaction has decreased to ≤Grade 1 in 
severity.  Monitor closely for any worsening.  If the reaction recurs, stop infusion.  
Protocol treatment will be discontinued.
NCI-CTCAE Grade 3 or Grade 4 allergic, infusion or hypersensitivity reaction or 
anaphylaxis
1. A Grade 3 hypersensitivity reaction consists of symptomatic bronchospasm requiring 
parenteral medications with or without urticaria, allergy-related edema/angioedema, 
or asymptomatic hypotension not requiring treatment.
2. A Grade 4 hypersensitivity reaction (ie, anaphylaxis) is a life-threatening event 
characterized by the same symptoms as in a Grade 3 reaction but also complicated by 
symptomatic hypotension or oxygen saturation of 70% or less.
Treatment of Grade 3 or Grade 4 allergic, infustion or hypersensitivity reaction or 
anaphylaxis
1. Stop the PF-05212384 infusion immediately and disconnect infusion tubing from the 
patient.
2. Administer epinephrine, bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc. as medically indicated.
3. Telephone Sponsor or designated representative to report an SAE and fax SAE 
worksheet.
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For a NCI-CTCAE Grade 3 or 4 hypersensitivity reaction, protocol treatment will be 
discontinued.
Re-treatment following Grade 1 or Grade 2 allergic, infustion or hypersensitivity 
reaction
1. Once the PF-05212384 infusion rate has been decreased due to a reaction, it will 
remain decreased for all subsequent infusions.
2. If the patient has a second reaction at the lower infusion rate, the infusion should be 
stopped and the patient should receive no further PF-05212384.
3. If the patient experiences a Grade 3 or 4 allergic reactionor anaphylaxis at any time, 
the patient should receive no further PF-05212384.
4. If there are questions concerning whether an observed reaction is consistent with an 
allergic reaction or anaphylaxis, the medical monitor should be contacted 
immediately to assist with grading the reaction.
PK and PD sampling should continue as long as the sampling does not interfere with the 
medical treatment of the patient.
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Appendix 11. BR23 English
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SAP_001.pdf: 
Protocol B2151002 Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol B2151002
A PHASE 1B OPEN-LABEL THREE-ARM MULTI-CENTER STUDY TO ASSESS 
THE SAFETY AND TOLERABILITY OF PF-05212384 (PI3K/MTOR INHIBITOR) 
IN COMBINATION WITH OTHER ANTI-TUMOR AGENTS
Statistical Analysis Plan
(SAP)
Version:
5
Author:
Date:
27-Nov-2017
33'
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TABLE OF CONTENTS 
LIST OF FIGURES ...................................................................................................................6
LIST OF TABLES.....................................................................................................................6
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................7
2. INTRODUCTION .................................................................................................................7
2.1. Study Design .............................................................................................................7
2.1.1. Overall Study Design....................................................................................7
2.1.2. Dose Levels to Be Tested (Dose Escalation)................................................8
2.1.3. Criteria for Dose Assignment.....................................................................10
2.1.3.1. Criteria for Dose Assignment for Arms A and B......................10
2.1.3.2. Criteria for Dose Assignment for Arm C..................................12
2.1.4. Safety and Efficacy Expansion in TNBC Arm B.......................................13
2.1.5. DLT Definition (All Arms) ........................................................................13
2.2. Study Objectives .....................................................................................................14
2.2.1. Primary Objectives .....................................................................................14
2.2.1.1. Original Protocol through Amendment 4..................................14
2.2.1.2. Amendment 5 (Expansion only) ...............................................14
2.2.2. Secondary Objectives .................................................................................14
2.2.2.1. Original Protocol through Amendment 4..................................14
2.2.2.2. Amendment 5 (Expansion only) ...............................................14
15
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING................................15
3.1. Unblinding...............................................................................................................15
3.2. Interim Analysis ......................................................................................................15
3.3. Final Analysis..........................................................................................................15
4. HYPOTHESES AND DECISION RULES.........................................................................15
4.1. Statistical Hypotheses .............................................................................................15
4.2. Statistical Decision Rules........................................................................................15
5. ANALYSIS SETS ...............................................................................................................15
5.1. Full Analysis Set .....................................................................................................15
5.2. Per Protocol Analysis Set (DLT Evaluable Set) .....................................................15
5.3. Safety Analysis Set..................................................................................................16
5.4. Other Analysis Sets .................................................................................................16
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5.4.1. Response Analysis Set................................................................................16
5.4.2. Pharmacokinetic Concentration Analysis Set.............................................16
5.4.3. Pharmacokinetic Parameter Analysis Set ...................................................16
5.4.4. Molecular Profiling Tumor Analysis Set....................................................16
5.4.5. Expression Tumor Analysis Set..................................................................16
5.4.6. Serum Pharmacodynamic Analysis Set......................................................16
17
17
5.4.9. QTc Analysis Set ........................................................................................17
5.4.10. PRO Analysis Set .....................................................................................17
5.5. Treatment Misallocations........................................................................................17
5.6. Protocol Deviations.................................................................................................17
5.6.1. Deviations Occurring Prior to Treatment Start...........................................17
5.6.2. Deviations Occurring Post-Treatment Start................................................18
6. ENDPOINTS AND COVARIATES ...................................................................................18
6.1. Efficacy Endpoint(s) ...............................................................................................18
6.1.1. Efficacy Endpoints for Patients WITH Measurable Disease in the 
Dose Escalation................................................................................................18
6.1.2. Efficacy Endpoints for Patients WITHOUT Measurable Disease in 
the Dose Escalation..........................................................................................19
6.1.3. Efficacy Endpoints for Patients in the Arm B Expansion Arms ................19
6.2. Safety Endpoints .....................................................................................................21
6.2.1. Treatment Emergent Adverse Events.........................................................21
6.2.2. Dose Limiting Toxicity – Primary Endpoint..............................................21
6.2.3. Safety Laboratory Tests..............................................................................21
6.2.4. Electrocardiogarm Endpoints .....................................................................21
6.2.5. Left Ventricular Ejection Fraction..............................................................22
6.2.6. Vital Signs ..................................................................................................22
6.2.7. ECOG Performance Status .........................................................................22
6.2.8. Pregnancy Test............................................................................................22
6.3. Other Endpoints.......................................................................................................22
6.3.1. Baseline Characteristics..............................................................................22
6.3.2. Treatment Administration...........................................................................23
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6.3.3. Pharmacokinetic Endpoints ........................................................................23
6.3.4. Molecular Profiling Biomarker Endpoints .................................................24
6.3.5. Expression Biomarker ................................................................................25
6.3.6. Serum Pharmacodynamic Endpoints..........................................................25
25
25
6.3.9. Patient Reported Outcomes ........................................................................25
6.3.9.1. EORTC QLQ-C30.....................................................................26
6.3.9.2. EORTC QLQ-BR23..................................................................26
6.4. Covariates................................................................................................................26
7. HANDLING OF MISSING VALUES ................................................................................26
7.1. Conventions for Missing Dates...............................................................................26
7.2. Missing Tumor Assessments...................................................................................27
7.3. Missing Data in Safety Endpoints...........................................................................27
7.3.1. Missing QTc Data.......................................................................................27
7.3.2. Missing Left Ventricular Ejection Fraction Data .......................................28
7.4. Missing Pharmacokinetic Data................................................................................28
7.4.1. Concentrations Below Limit of Quantification ..........................................28
7.4.2. Deviations, Missing Concentrations and Anomalous Values.....................28
7.4.3. Pharmacokinetic Parameters.......................................................................28
7.5. Missing Patient Reported Outcome Data................................................................28
7.6. Missing Biomarker Data .........................................................................................29
7.6.1. Handling of Duplicate Biomarker Data......................................................29
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................29
8.1. Statistical Methods ..................................................................................................29
8.2. Statistical Analyses .................................................................................................29
8.2.1. Analyses of Primary Endpoint....................................................................30
8.2.1.1. Dose escalation..........................................................................30
8.2.1.2. Arm B Expansion......................................................................30
8.2.2. Analysis of Safety Endpoints......................................................................30
8.2.2.1. Summaries of Adverse Events ..................................................30
8.2.2.2. Analyses of Laboratory Tests....................................................32
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8.2.2.3. Hy’s Law Listing.......................................................................32
8.2.2.4. Analyses of Electrocardiogram Endpoints................................32
8.2.2.5. Left Ventricular Ejection Fraction (Arm C Only).....................33
8.2.2.6. Listings for Safety Endpoints....................................................33
8.2.3. Analyses of Study Conduct ........................................................................34
8.2.4. Analyses of Baseline Characteristics..........................................................34
8.2.4.1. Demographic Characteristics and Primary Diagnosis 
Related Characteristics ......................................................................34
8.2.4.2. Medical History.........................................................................35
8.2.4.3. Prior Drugs Taken and Prior Non-Drug Treatment ..................35
8.2.5. Treatment Descriptions...............................................................................35
8.2.5.1. Treatment Administration .........................................................36
8.2.5.2. Concomitant Medications and Non-Drug Treatments ..............37
8.2.6. Analyses of Pharmacokinetics....................................................................37
8.2.6.1. Pharmacokinetic Concentrations...............................................37
8.2.6.2. Pharmacokinetic Parameters .....................................................38
8.2.7. Analyses of Additional Efficacy.................................................................38
8.2.7.1. Dose Escalation.........................................................................38
8.2.7.2. Expansion..................................................................................38
8.2.7.3. Listings of Efficacy Endpoints for All Patients ........................39
8.2.8. Patient Reported Outcomes ........................................................................39
8.2.9. Analysis of Biomarkers ..............................................................................40
8.2.9.1. Analyses of Molecular Profiling Biomarkers............................40
8.2.9.2. Analyses of Expression Biomarkers .........................................41
8.2.9.3. Analyses of Serum Pharmacodynamic (PD) Biomarkers .........42
 
42
43
43
9. REFERENCES ....................................................................................................................44
10. APPENDICES ...................................................................................................................45
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LIST OF FIGURES
Figure 1.  Overall Dose Escalation Design................................................................................8
Figure 2. Recommended Action Based on Cumulative Dose Limiting Toxicities at 
Current Dose Level (Arms A and B)....................................................................11
LIST OF TABLES
Table 1. Dose Levels for Arms A, B and C...............................................................................9
Table 2. Dose Escalation Sequence (Arm C)...........................................................................12
Table 3. Pharmacokinetic Parameters to Be Calculated..........................................................24
Table 4.  Summary Statistics to Be Calculated for Pharmacokinetic Parameters ...................38
APPENDICES
Appendix 1. DATA DERIVATION DETAILS ......................................................................45
Appendix 1.1. Definition and Use of Visit Windows in Reporting.........................................45
Appendix 2. STATISTICAL METHODOLOGY DETAILS..................................................47
Appendix 2.1. Interval Design for Arms A and B...................................................................47
Appendix 2.2. Definition of Progression-Free Survival (Expansion only) .............................52
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Amendment 1 (SAP version 2) was for updates based on protocol amendments through 
amendment 3.  The dose levels for PF-05212384 were increased.
Amendment 2 (SAP version 3) is for Protocol Amendment 5.  Two expansion arms are added 
to Arm B in TNBC patient.  The SAP amendment also makes updates to be consistent with 
the protocol.
In addition, for SAP version 3, all biomarker and pharmacodynamics analyses have been
removed from this SAP and will be contained in a separate supplemental SAP.
SAP version 4 updates the PFS definition to take into account an extended time between 
tumor assessments after a patient was on study for 13 cycles, per the protocol.
SAP version 5 re-incorporates the biomarker and pharmacodynamics analyses into the SAP.
2. INTRODUCTION
2.1. Study Design
2.1.1. Overall Study Design
This is a Phase 1b, three-arm, open-label, multi-center, multiple dose, dose escalation, safety, 
tolerability, pharmacokinetic and pharmacodynamic study of PF-05212384 in combination 
with anti-tumor agents in sequential cohorts of adult patients with select advanced solid 
tumors.  Successive cohorts of patients will receive selected doses of PF-05212384 in 
combination with selected doses of chemotherapeutic agents or dacomitinib in 3 independent 
arms on an outpatient basis. 
The three arms will be designated Arms A, B and C.
A modified toxicity probability interval (mTPI) method with adjustment based on observed 
DLT rate will be used to guide the dose assignment in Arms A and B.1,2 The actual dose 
selected for the next cohort will take into account the recommended dose by using the 
adjusted mTPI method as well as safety data other than dose limiting toxicities (DLTs). 
In Arm C, a zone-based design will be utilized, which is a modified 3+3 design that 
potentially allows opening of more than one dose level at the same time.3
In all arms, dose escalation will proceed until a maximum tolerated dose (MTD) or MTDs 
are declared, or the Maximum Allowable Dose (the highest planned dose) is reached.
For Arm A and B it is expected that 10-15 patients will be treated at the MTD during dose 
finding.  In Arm C, a minimum of 10 and maximum of 15 patients will be treated at the MTD 
to further confirm safety and tolerability and to explore early signs of efficacy.  Per Protocol 
Amendment 5, there will be an expansion cohort in Arm B for TNBC patients.  It is planned 
that 30 response evaluable patients will be enrolled, 15 patients into each of the 2 arms (1st
line and 2nd/3rd line).
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Each of the treatment arms are restricted to patients with tumor types for which the 
combination partner is either considered standard of care, or in the case of dacomitinib, are 
indications which have been shown to be sensitive. 
The overall study design is show in Figure 1.
Figure 1.  Overall Dose Escalation Design
In the dose escalation, to understand the single-dose safety and single dose pharmacokinetics 
(PK) of the study drug, a lead-in period will be included.  A single lead-in dose of 
PF-05212384 will be given either 7 days prior to Cycle 1 Day 1 (Arms A and B) or 14 days 
prior to Cycle 1 Day 1 (Arm C).  The lead-in period duration, subsequent doses, regimens 
and PK time points may be modified based on the PK profile observed during the lead-in 
period.  Patients will then receive study treatment on an outpatient basis in 21 day cycles. 
The expansion arms do not have a lead-in dose, PK assessments will begin on Cycle 1 Day 1.
Treatment with study drug will continue until progression of disease, uncontrollable toxicity, 
a decision by the patient or Investigator to discontinue treatment, or the study is terminated.  
Patients experiencing toxicity or a DLT may be managed with dose modification or 
discontinuation.  If a patient discontinues PF-05212384 or the combination partner, 
continuation within the study will be discussed with the Sponsor. 
2.1.2. Dose Levels to Be Tested (Dose Escalation)
The possible dose levels for Arms A, B, and C dose escalation are shown in Table 1.  For 
Arms A and B, dose levels differ only in the dose of PF-05212384.  For Arm C, dose levels 
differ for PF-05212384 and dacomitinib. 
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Table 1. Dose Levels for Arms A, B and C
Arm A
Dose Level
PF-05212384 mg/wk
IV
Docetaxel mg/m2 IV q 3 wks
A(-1)
75
75
A1#
90
75
A2
110
75
A3
130
75
A4
150
75
A5
180
75
A6
215
75
A7
260
75
A8
310
75
#  Starting dose level.
Arm B
Dose Level
PF-05212384 mg/wk
IV
Cisplatin mg/m2 IV q 3wks
B(-1)
75
75
B1#
90
75
B2
110
75
B3
130
75
B4
150
75
B5
180
75
B6
215
75
B7
260
75
B8
310
75
#  Starting dose level.
Arm C
Dose Level
PF-05212384 mg/wk
IV
Dacomitnib PO mg qd
C1#
90
30
C1h
90
45
C2
110
30
C2h*
110
45
C3
130
30
C3h*
130
45
C4
150
30
C5
180
30
C6
215
30
C7
260
30
C8
310
30
#  Starting dose level.
*dose level will not be explored since dose level exceeds MTD
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2.1.3. Criteria for Dose Assignment
2.1.3.1. Criteria for Dose Assignment for Arms A and B 
In Arms A and B, the dose assignment recommendations of the method are provided in 
Figure 2.  Patients will be enrolled in cohorts of 3 patients, with the flexibility of other cohort 
sizes.  The starting dose levels will be A1 and B1 for Arms A and B, respectively.  For any 
subsequent cohort of patients, the recommended dose assignment action will be based on the 
total number of patients with DLTs among all patients treated at the current dose level.  For 
example, if a cohort of 3 patients are treated at dose level A1 for the first time and one of the 
patients experience a DLT, then it is recommended that the next cohort of patients stay at the 
current dose level (S); if this recommendation is accepted, then the selected dose level for the 
next cohort of patients will be A1; if a cohort of 3 additional patients are treated at dose level 
A1 and no additional DLTs are observed, then the cumulative number of patients treated at 
A1 is 6, and the cumulative number of patients with DLTs at A1 is 1, thus the 
recommendation would be to escalate the dose for the subsequent cohort (E).
Details of the interval design to be used for Arms A and B in this study are provided in 
Appendix 2.1.
The actual dose level selected for the next cohort of patients will take into account the 
recommended dose level and all available safety data other than DLTs.  Dose finding for an 
arm may be stopped when one of the following criteria is met:
•
The lowest dose level appears too toxic after at least 3 patients are dosed at that dose 
level.
•
The maximum sample size in dose finding of 40 evaluable patients per arm has been 
reached.
•
A minimum of 10 evaluable patients have been treated at the estimated MTD. 
For Arms A and B, if the DLT rates are not monotonically increasing the MTD will be 
estimated based on isotonic regression of DLT rates of all dose levels at the end of the study.  
The MTD will be the dose that has a DLT rate that is less than or equal to 32%.  Up to a 
maximum of 15 patients will be treated at the MTD during dose finding to define the 
tolerability and to evaluate clinical activity.
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Figure 2. Recommended Action Based on Cumulative Dose Limiting Toxicities at 
Current Dose Level (Arms A and B)
Cumulative number of patients treated at the current dose level
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cumulative number of patients with DLTs at 
the current dose level
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
S
E
E
E
E
E
E
E
E
E
E
2
D
D
D
D
D
S
S
S
S
E
E
E
E
E
3
DU
DU
DU
D
D
D
D
S
S
S
S
S
S
4
DU
DU
DU
DU
DU
D
D
D
D
S
S
S
5
DU
DU
DU
DU
DU
DU
D
D
D
D
D
6
DU
DU
DU
DU
DU
DU
DU
DU
D
D
7
DU
DU
DU
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
DU
12
DU
DU
DU
DU
13
DU
DU
DU
14
DU
DU
15
DU
E = Escalate to the next higher dose level
S = Stay at the current dose level
D = De-escalate to the next lower dose level
DU = The current dose level is unacceptably toxic and should be eliminated from further testing
Target DLT rate = 25%
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2.1.3.2. Criteria for Dose Assignment for Arm C
The starting dose level will be C1.  Dose escalation will proceed according to the sequence in 
Table 2 until an MTD (or two MTDs) is declared.
Table 2. Dose Escalation Sequence (Arm C)
Arm C
Dacomitinib PO
mg qd
30
45
PF-05212384 mg/wk IV
90
C1#
C1h
110
C2
C2h*
130
C3
C3h*
150
C4
180
C5
215
C6
260
C7
310
C8
# Starting dose level.
*C2h and C3h from the original protocol will not be pursued due 
to observing 2 DLTs in dose level C1h.
As in a classical 3+3 design, dose escalation is indicated if there is no DLT in 3 patients or 
≤1 DLT in 6 patients at the current dose level.  If DLT data at dose level C1 indicates dose 
escalation, then two separate dose escalations from C1 to C2 and from C1 to C1h may occur 
simultaneously (see Table 2).  To open enrollment to dose level C2h, the DLT data from the 
preceding two lower dose levels C2 and C1h must both indicate dose escalation, ie, no DLTs 
were observed in 3 patients or ≤1 DLT in 6 patients for each of them. 
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At each dose level, up to 3 patients will be enrolled initially and evaluated for DLT.  
Subsequent dose levels may not be opened until all patients entered at the current dose level 
have been treated and observed for at least one complete cycle and the number of DLTs 
among those patients in their first cycle has been determined.  Patients not evaluable for 
assessment of DLT may be replaced.  Dose escalation will continue until the Maximum 
Allowable Dose level is reached or until DLTs are observed in at least 2 of the 3-6 patients 
treated at a dose level, leading to the conclusion that an MTD has been exceeded.  The 
planned cohort size is 3-6 patients per dose cohort however, based upon observed toxicity or 
unexpected clinical findings, individual dose cohorts may be expanded beyond 6 patients 
after discussion and review by the Sponsor’s medical monitor and the Investigators.  When a 
dose level exceeding an MTD has been identified, the next lower dose level is declared the 
MTD if 6 patients have already been treated at that dose level.  Otherwise 3 additional 
patients are treated at the next lower dose level, and if none or 1 patient experiences DLTs 
that dose level is declared the MTD.
For Arm C, it is possible that more than one MTD is identified.  In such case, the Sponsor in 
agreement with the Investigators will decide, based on all available data, the most rational 
dose level to enroll additional patients in an expansion cohort.  Up to a maximum of 
15 patients will be treated in the expansion cohort to better define the tolerability and to 
evaluate clinical activity.
It is expected that up to 50 patients will be enrolled into Arm C, including the MTD 
expansion cohort.
2.1.4. Safety and Efficacy Expansion in TNBC Arm B
An expansion cohort will open with implementation of Protocol Amendment 5 to assess the 
clinical activity and continued overall safety profile of PF-05212384 in combination with 
cisplatin in patients with TNBC at the 180mg PF-05212384 dose in combination with 
cisplatin at 75 mg/m2.  There will be two arms: Arm 1 for 1st line TNBC patients and Arm 
2 for 2nd/3rd line TNBC patients.
Treatment in the expansion portion of the study will continue until progression of disease, 
uncontrollable toxicity, a decision by the patient or Investigator to discontinue treatment, or 
the study is terminated.
Up to 15 response evaluable patients (see Section 5.4.1) per arm will be treated in the 
expansion.
2.1.5. DLT Definition (All Arms)
Refer to the protocol for the definition of DLT in this study.
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2.2. Study Objectives
2.2.1. Primary Objectives
2.2.1.1. Original Protocol through Amendment 4
•
To assess the safety and tolerability and to estimate the MTD of the following 
combinations in patients with advanced solid tumors:
•
Arm A: PF-05212384 and docetaxel;
•
Arm B: PF-05212384 and cisplatin;
•
Arm C: PF-05212384 and dacomitinib.
2.2.1.2. Amendment 5 (Expansion only)
•
To evaluate the anti-tumor activity of PF-05212384 plus cisplatin in patients with 
TNBC.
2.2.2. Secondary Objectives 
2.2.2.1. Original Protocol through Amendment 4
•
To evaluate the overall safety profile.
•
To assess the effects of PF-05212384 on the pharmacokinetics of docetaxel, cisplatin 
and dacomitinib and vice versa in Arms A, B, and C respectively.
•
To evaluate possible biomarkers of efficacy (eg, KRAS mutation) and 
pharmacodynamic (PD) effects in paired tumor biopsies (eg, pAkt levels) and serum 
(eg, insulin levels).
•
To characterize the effects of the combinations on the potential to prolong the QTc 
interval.
•
To document anti-tumor activity.
2.2.2.2. Amendment 5 (Expansion only)
•
To continue to evaluate the overall safety profile of the combination of 
PF-05212384 plus cisplatin.
•
To characterize single and multiple dose pharmacokinetics following IV 
administration of PF-05212384.
•
To characterize the effects of the combinations on the potential to prolong the QTc
interval.
•
To evaluate additional anti-tumor activity.
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•
To assess patient reported outcomes (PRO) of global quality of life (QOL) and 
disease/treatment-related symptoms of advanced breast cancer.
 
 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
3.1. Unblinding
This is an open label study, thus unblinding is not applicable.
3.2. Interim Analysis
There is no official interim analysis.
3.3. Final Analysis
The final analysis will be performed at the time of official database release for clinical study 
report unless if there are ongoing patients in which case a final CSR will be written with a 
supplemental CSR to follow.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There are no formal statistical hypotheses.
4.2. Statistical Decision Rules
There are no formal statistical decision rules.
5. ANALYSIS SETS
5.1. Full Analysis Set
The full analysis set includes all enrolled patients. 
5.2. Per Protocol Analysis Set (DLT Evaluable Set)
The per protocol analysis set includes all enrolled patients who receive at least one dose of 
study medication and who do not have major treatment deviations during the first cycle.  
Patients with major treatment deviations in Cycle 1 are not evaluable for DLT and may be 
replaced.  Major deviations include:
•
Administration of less than 75% of the planned Cycle 1 dose of either study drug in 
the combination (provided that the reduction is not due to toxicity attributable to the 
combination).
•
Administration of more than 125% of the planned Cycle 1 dose of either study drug 
in the combination.
&&,
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5.3. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
medication. 
5.4. Other Analysis Sets
5.4.1. Response Analysis Set
The response analysis set consists of all patients who receive at least one dose of study 
medication, have the disease under study, and who have an adequate baseline tumor 
assessment (see Appendix 1 for details). 
5.4.2. Pharmacokinetic Concentration Analysis Set
The PK concentration analysis set is defined as all enrolled patients who start treatment and
who have concentration measurement recorded for at least one time point.
5.4.3. Pharmacokinetic Parameter Analysis Set
The PK parameter analysis set is defined as all enrolled patients who start treatment and who 
have sufficient information to estimate at least 1 of the PK parameters of interest.
•
Patients with a change to the planned PF-05212384 30 minute infusion time (eg, 
increasing to 60 minutes), will not be included in the summary statistics for PK 
parameters and will be listed separately.
5.4.4. Molecular Profiling Tumor Analysis Set 
The molecular profiling tumor analysis set is defined as all enrolled patients who start 
treatment and have baseline archived tumor biopsy formalin fixed paraffin embedded (FFPE) 
sample (or fresh FFPE if archived is not available) successfully analyzed for at least one of 
the selected biomarkers. 
5.4.5. Expression Tumor Analysis Set
The expression tumor analysis set is defined as all enrolled patients who start treatment and 
have both baseline and on-treatment optional fresh FFPE tumor biopsy samples successfully 
analyzed for at least one of the selected biomarkers.
Selected biomarkers include those related to pathway inhibition (pharmacodynamics) and 
resistance signaling.
5.4.6. Serum Pharmacodynamic Analysis Set
The serum PD analysis set is defined as all enrolled patients who start treatment and have a 
baseline and at least one post-baseline measurement for at least one serum PD biomarker. 
PD biomarkers include serum glucose, insulin, and HbA1c from safety laboratory tests.
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5.4.9. QTc Analysis Set
The QTc analysis set is defined as all enrolled patients who have at least one ECG 
assessment after receiving study drug or study drugs.  Analyses of changes from baseline 
also require a baseline ECG assessment.
For the purpose of QTc versus concentration analysis, the analysis set is defined as all 
enrolled patients who have at least one of the planned time matched PK concentration and 
ECG assessments. 
5.4.10. PRO Analysis Set
The PRO analysis set is defined as all enrolled patients who started treatment on study drug 
and who completed a baseline assessment and at least one post-baseline assessment.
The PRO analysis set will be the primary dataset to determine change from baseline scores 
and the proportion of patients with scores that improved, worsened, or remained stable over 
treatment.
5.5. Treatment Misallocations 
Patients will be analyzed based on the arm to which they are initially assigned unless the 
following occurs:
•
Assigned but not treated: they will not be included in safety or efficacy analyses.
•
Assigned but received/took incorrect treatment (ie, wrong arm or wrong dose 
level): they will be reported under the treatment they actually received for safety and 
efficacy analyses (ie, as treated).
5.6. Protocol Deviations
The following describes any protocol deviations that relate to the statistical analyses or 
analysis sets.
5.6.1. Deviations Occurring Prior to Treatment Start
Pre-treatment deviation affecting the response analysis set: patients who are found to have
inadequate baseline assessment.  Refer to Section 5.4.1 for handling of these deviations.
&&,
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5.6.2. Deviations Occurring Post-Treatment Start
Major post-treatment start deviation affecting the safety analysis set: patients received 
incorrect treatment.  Refer to Section 5.5 for handling of these deviations.
Major post-treatment start deviations affecting the per protocol analysis set include: 1) 
patients received less than 75% of the planned Cycle 1 dose of either study drug in the 
combination (provided that the reduction is not due to toxicity attributable to the 
combination), and 2) patients received more than 125% of the planned Cycle 1 dose of either 
study drug in the combination.  Refer to Section 5.2 for handling of these deviations.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
Efficacy endpoints are defined differently for patients without measurable disease at baseline 
compared to those with measurable disease at baseline.  Efficacy is a primary endpoint for 
the Arm B expansion arms and secondary endpoint for the dose escalation arms.  Patients in 
the expansion arms are required to have measureable disease and to have responses 
confirmed.
6.1.1. Efficacy Endpoints for Patients WITH Measurable Disease in the Dose Escalation
Objective response status at each evaluation [complete response (CR), partial response (PR), 
stable disease (SD), progressive disease (PD), or indeterminate] will be assessed by the 
Investigator according to the RECIST v1.1 guidelines.
Best overall response is defined as the best response recorded from first dose of study 
treatment until disease progression.  It is derived from the sequence of objective statuses.  
Objective statuses after the first PD or the start of a new anticancer treatment are excluded 
from consideration.  Categories include CR, PR, SD, PD and indeterminate ( not evaluable). 
•
CR:  At least one objective status of CR documented before progression;
•
PR:  At least one objective status of PR documented before progression, but not 
qualifying as CR;
•
SD: At least one objective status of SD documented at least 6 weeks after first dose of 
study treatment and before progression, but not qualifying as CR, or PR.  (note: 
6 weeks is chosen based on the first post-baseline tumor assessment scheduled at 
6 weeks from C1D1, adding at least 1 week between lead-in dose and C1D1, and
allowing 5 days early for the first post-baseline tumor assessment);
•
PD:  Objective status of progression within 15 weeks of first dose of study treatment, 
not qualifying as CR, PR, or SD. (note: 15 weeks is chosen based on the second 
post-baseline tumor assessment scheduled at 12 weeks from C1D1, adding up to 
2 weeks between lead-in dose and C1D1, and allowing 5 days delay for the second 
post-baseline tumor assessment);
•
Indeterminate:  Progression not documented within 15 weeks of first dose of study 
treatment and no other response category applies.
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Objective response is defined as CR or PR. 
Clinical benefit response is defined as CR or PR at any time, or non-CR/non-PD or SD for 
at least 24 weeks from first dose of study treatment. 
For tumor measurements, in the event that a lesion is “too small to measure” a measurement 
of 5 mm will be used for calculations to assess best overall response.
6.1.2. Efficacy Endpoints for Patients WITHOUT Measurable Disease in the Dose
Escalation
Objective response status at each evaluation (CR, PD, non-CR/non-PD, or indeterminate)
will be assessed by the Investigator according to the RECIST v1.1 guidelines. 
Best overall response is defined as the best response recorded from first dose of study 
treatment until disease progression.  It is derived from the sequence of objective statuses.  
Objective statuses after the first PD or the start of a new anticancer treatment are excluded 
from consideration.  Best overall responses will include the following categories: CR, 
non-CR/non-PD, PD, and Indeterminate.
•
CR: At least one objective status of CR documented before progression.
•
Non-CR/non-PD: At least one objective status of non-CR/non-PD documented at 
least 6 weeks after first dose of study treatment and before progression, but not 
qualifying as CR.
•
PD: Objective status of progression within 15 weeks of first dose of study treatment, 
not qualifying as CR, or non-CR/non-PD.
•
Indeterminate: Progression not documented within 15 weeks of first dose of study 
treatment and no other response category applies.
6.1.3. Efficacy Endpoints for Patients in the Arm B Expansion Arms
Objective response status at each evaluation [complete response (CR), partial response (PR), 
stable disease (SD), progressive disease (PD), or indeterminate] will be assessed by the 
Investigator according to the RECIST v1.1 guidelines.
Best overall response is defined as the best response recorded from first dose of study 
treatment until disease progression.  It is derived from the sequence of objective statuses.  
Objective statuses after the first PD or the start of a new anticancer treatment are excluded 
from consideration.  Categories include CR, PR, SD, PD and indeterminate (inevaluable).
•
CR: Two objective statuses of CR a minimum of four weeks apart documented 
before progression and start of new anti-cancer therapy.
•
PR: Two objective statuses of PR or better (PR followed by PR or PR followed by 
CR) a minimum of four weeks apart documented before progression and start of new 
anti-cancer therapy, but not qualifying as CR.  Sequences of PR- Stable- PR are 
considered PRs as long as the two PR responses are observed at a minimum of 
4 weeks apart.
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•
SD: At least one objective status of SD documented at least 6 weeks after first dose of 
study treatment and before progression and the start of new anti-cancer therapy, but 
not qualifying as CR, or PR.  An assessment window of -5 days is allowed per the 
protocol to still qualify as SD.
•
PD: Objective status of progression within 13 weeks of first dose of study treatment, 
not qualifying as CR, PR, or SD (note that 13 weeks is chosen based on 2 tumor 
assessments and to allow for ~5 days delay for the second post-baseline tumor 
assessment per the protocol).
•
Indeterminate: Progression not documented within 13 weeks of first dose of study 
treatment and no other response category applies.
Objective response is defined as CR or PR. 
Clinical benefit response is defined as CRor PR at any time, or non-CR/non-PD or SD for at 
least 24 weeks from first dose of study treatment. 
Progression-free survival (PFS) is defined as the time from first dose of study treatment to 
date of first documentation of progression or death due to any cause, whichever occurs first.  
Documentation of progression must be by objective disease assessment as defined by 
RECIST v1.1.
Patients last known 1) to be alive, 2) not to have started new anti-cancer treatment, and 3) to 
be progression-free, and who have a baseline and at least one on-study disease assessment, 
will be censored at the date of the last objective disease assessment that verified lack of 
disease progression. 
Patients with inadequate baseline disease assessment will be censored at the date of first dose 
of study treatment.
Patients with no on-study disease assessments will be censored at the date of first dose of 
study treatment unless death occurred prior to 13 weeks since first dose (in which case the 
death is an event). 
Patients starting new anti-cancer treatment prior to progression will be censored at the date of 
last objective disease assessment documenting no progression prior to the new treatment. 
Patients with documentation of progression or death after an unacceptably long interval 
(>13 weeks within the first 12 cycles or > 19 weeks from cycle 13 on) since the last tumor 
assessment will be censored at the time of last objective assessment documenting no 
progression.
Censoring and Event details are listed in Appendix 2.2. 
For tumor measurements, in the event that a lesion is “too small to measure” a measurement 
of 5 mm will be used for calculations to assess best overall response.
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6.2. Safety Endpoints
6.2.1. Treatment Emergent Adverse Events
Adverse Events (AEs) will be graded by the Investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 and coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
Causal relationship of an AE to study treatment will be assessed by the investigator.  As there 
are two study drugs, an AE may be attributed to either or both of the study drugs.
An adverse event is a treatment-emergent adverse event (TEAE) if:
•
The event occurs for the first time after the start of study treatment and within 28 days 
after final dose of study treatment and was not seen prior to the start of treatment, or;
•
The event was seen prior to the start of study treatment but increased in CTCAE 
grade after the start of study treatment and within 28 days after final dose of study 
treatment.
6.2.2. Dose Limiting Toxicity – Primary Endpoint
A DLT is any of the TEAEs meeting the DLT criteria as specified in the protocol that occurs
in the first cycle of treatment (starting from the lead-in dose through Cycle 2 Day 1 for this 
purpose) which are possibly attributable to the study drugs.
DLT is the primary endpoint of the dose escalation portion of the study.
6.2.3. Safety Laboratory Tests 
Safety laboratory tests include the following categories: hematology, blood chemistry, 
urinalysis, and coagulation.  They will be collected at screening and frequently during the 
study.
Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03) grades will be 
assigned programmatically to the laboratory test data, as appropriate.
See Appendix 1 for definition of baseline safety laboratory values.
6.2.4. Electrocardiogarm Endpoints
For Arms A and B, ECG endpoints will be obtained at Screening, Cycle 1 Day 2, and 
Cycle 2 Day 1.
For Arm C, ECG endpoints will be collected at screening, Cycle 1 Day 2, Cycle x 
Day 1 (x>1), and the end of treatment.
For Arm B expansion, ECG endpoints will be Screening, Day 1 of all Cycles
(pre-PF-05212384 infusion and immediately prior to completion of PF-05212384 infusion), 
and End of Treatment Visit.
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ECG endpoints include heart rate (HR), RR, PR, QRS, and QT.  Fridericia's correction of QT 
interval (QTcF) will be calculated programmatically as QT/(RR)1/3.  If QTc is reported by 
sites on CRF, it will be designated QTc.  Other corrections for QT interval may be 
considered if necessary.
See Appendix 1 for definition of baseline ECG values.
6.2.5. Left Ventricular Ejection Fraction
Left ventricular ejection fraction (LVEF) will be measured at baseline, the end of Cycle 3, 
end of Cycle 6, and then every 6 cycles for Arm C patients only.
LVEF may be measured by either echocardiogram (ECHO) or multi-gated radionuclide study 
(MUGA).  However, all values for a patient should be from the same method.
See Appendix 1 for definition of baseline LVEF values.
6.2.6. Vital Signs
Vital signs will be obtained at screening and frequently during the study.
6.2.7. ECOG Performance Status
Performance status will be obtained at screening and frequently during the study.
See Appendix 1 for definition of baseline ECOG values.
6.2.8. Pregnancy Test
For female patients of childbearing potential, serum or urine pregnancy test will be 
performed twice prior to starting study treatment and repeatedly while on study.
6.3. Other Endpoints
6.3.1. Baseline Characteristics
The baseline characteristics include:
•
Age;
•
Sex;
•
Race;
•
Height;
•
Weight;
•
Performance status;
•
Primary diagnosis;
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•
Time from [histopathological] diagnosis to first dose of treatment;
•
Number of prior systemic therapies;
•
Number of prior surgeries;
•
Prior radiotherapy (yes/no);
•
Measurable disease (lesions) present (yes, no);
•
Involved disease sites.
6.3.2. Treatment Administration
Duration of treatment = date of last dose – date of first dose +1.
A dose reduction is a decrease in the prescribed dose.
Missed dose (dacomitinib only): A missed dose is an occurrence of total daily dose of 0 mg 
during treatment starting from Cycle 1 Day 1.  If “the total number of doses missed on 
UNKNOWN dates” is >0, missed doses are also indicated and should be counted towards the 
total number of missed doses.
Missed dose (PF-05212384, irinotecan, cisplatin): A missed dose is a 0mg total daily dose for 
a protocol planned dosing day.  In the event that a dosing record is recorded as “Not Done”, 
this will be considered as a missed dose.
6.3.3. Pharmacokinetic Endpoints 
Blood samples for PK analysis will be taken according to the Schedule of Study Treatment 
and Pharmacokinetic Assessments described in the protocol.
Table 3 shows the PK parameters that will be calculated for PF-05212384, docetaxel, 
cisplatin, and dacomitinib from the plasma concentration-time data using standard 
non-compartmental methods.
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Table 3. Pharmacokinetic Parameters to Be Calculated
Plasma PF-05212384 (Arms A, B, and C)
PK Parameter
Lead-in** 
(single dose)
Cycle 2, Day 
1 (steady state)
AUCinf
*
X
AUClast
X
AUCĲ
X
X
Cmax
X
X
Tmax
X
X
Cmin
X
Cav
X
t1/2
*
X
X
CL*
X
X
Vss
*
X
X
Rac
X
* If data permit.
** Lead-in = 7 days prior to Cycle 1 in Arms A and B of the dose escalation; 14 days prior to Cycle 1 in Arm C
of the dose escalation. PK will be obtained for PF-05212384 on Cycle 1 Day 1 and Cycle 2 Day 1 in the 
Expansion Phase of B2151002.
Plasma Docetaxel (Arm A), Cisplatin (Arm B), and Dacomitinib (Arm C)
PK Parameter
Arm A
Plasma Docetaxel
(single dose)
Arm B
Plasma Cisplatin 
(single dose)
Arm C
Plasma Dacomitinib 
(steady state)
AUCinf
*
x
x
AUClast
x
x
AUCĲ
x
Cmax
x
x
x
Tmax
x
x
x
* If data permit.
Note: Parameters to be calculated for Cycle 1 Day 2 and Cycle 2 Day 1.  PK will not be obtained for Cisplatin 
in the Expansion Phase of B2151002.
6.3.4. Molecular Profiling Biomarker Endpoints
For dose escalation 
 all patients will be 
required to provide an archived tumor biopsy FFPE sample.  If an archived tumor sample is 
not available, patients must consent to provide a fresh biopsy FFPE for purpose of this 
analysis. 
Endpoints include gene mutation status (eg, presence or absence of mutations (ie, 
PI3KCA/KRAS/BRAF) as well as specific mutation(s) found such as KRAS G12D).
  
&&,
&&,
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6.3.5. Expression Biomarker
Fresh FFPE tumor biopsies will be requested at Screening and on Cycle 2 Day 8 for all 
patients in the dose escalation, and are mandatory for patients in the MTD cohort in Arm C 
and for patients assigned a preliminary MTD in Arms A and B dose escalation.  Optional 
tumor biopsies are also collected at the End of Treatment visit. 
 
 
 
6.3.6. Serum Pharmacodynamic Endpoints
These endpoints are blood chemistry tests to be used for pharmacodynamic assessment.  
They include the following: serum glucose, insulin, and HbA1c, typically expressed as 
units/mL, or some variation thereof.  These are collected at baseline (within 14 days of first 
dose) and multiple times on study.
 
 
 
 
 
 
 
 
 
6.3.9. Patient Reported Outcomes
Patient reported outcomes of functioning, global quality of life and breast cancer symptoms 
will be assessed using the EORTC QLQ-C30 and its breast cancer module EORTC 
QLQ-BR23
Patients will complete each instrument at pre-dose for the following time points: baseline, on 
Day 1 and Day 8 of cycles 1 and 2, on Day 1 of each subsequent cycle starting with Cycle 3, 
and then at the end of treatment visit.  Completed questionnaires are always considered 
source document and must be filed accordingly.
&&,
&&,
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6.3.9.1. EORTC QLQ-C30
The EORTC-QLQ-C30 (see Protocol Appendix 10) is a 30-item questionnaire composed of 
five multi-item functional subscales (physical, role, emotional, cognitive, and social 
functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global 
quality of life (QOL) subscale, and six single item symptom scales assessing other 
cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, 
and the financial impact of cancer).  The questionnaire employs 4-point Likert scales with 
responses from “not at all” to “very much” for most of the items and 7-point Likert scales for 
global health and overall QOL.6 Responses to all items are then converted to a 0 to 
100 scale.  For functional and global QOL scales, higher scores represent a better level of 
functioning/QOL.  For symptom-oriented scales, a higher score represents more severe 
symptoms.  A 10-point or higher change in scores from baseline is considered clinically 
significant.
6.3.9.2. EORTC QLQ-BR23
The EORTC-QLQ-BR23 (see Protocol Appendix 11) is a 23-item breast cancer-specific 
companion module to the EORTC-QLQ-C30 and consists of four functional scales (body 
image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales 
(systemic side effects, breast symptoms, arm symptoms, upset by hair loss).
The subscales of the EORTC QLQ-C30 and the QLQ-BR23 will be scored based on the 
EORTC scoring manual.7 Scales will utilize all completed items to derive the score of each 
scale.  For the EORTC QLQ-C30 and BR-23 in cases where two answers are given to one 
item, the more severe answer will be counted.  If less than half of the constituent items on the 
QLQ-C30 and QLQ-BR 23 have been answered for a multi-item subscale, that subscale will 
be considered missing.  Single-item subscales will be considered missing if the constituent 
item is incomplete
In summary, each scale of the EORTC QLQ-C30 and the QLQ-BR23 will be transformed so 
that scale scores will range from 0 to 100.  The transformation will proceed in two steps.  
First, the average of the items contributing to a subscale will be calculated to compute the 
raw score of the scale.  Next, a linear transformation will be applied to ‘standardize’ the raw 
score.  After scores are transformed, higher scores on the EORTC QLQ-C30 or the 
QLQ-BR23 will represent higher (“better”) levels of functioning and/or a higher (“worse”) 
level of symptoms.
6.4. Covariates 
N/A
7. HANDLING OF MISSING VALUES
7.1. Conventions for Missing Dates
In compliance with Pfizer Data Standards (PDS), if the day of the month is missing for any 
date used in a calculation, the 1st of the month will be used to replace the missing date unless 
the calculation results in a negative time duration (eg, date of resolution cannot be prior to 
date of onset; if replacing resolution date with the 1st of the month results in a negative 
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duration, the resolution date will be set to the onset date).  Similarly, if the month and day of 
the month are missing for any date used in a calculation, the 1st of the month of January will 
be used to replace the missing date unless the calculation results in a negative time duration. 
For adverse events, onset date and stop date will be imputed based on the PDS standard 
algorithms to ensure that if the onset date is missing for an AE, the AE is considered to be 
treatment emergent unless the collection date is prior to the treatment start date.
7.2. Missing Tumor Assessments
If baseline tumor assessment is inadequate, the patient cannot be assessed for response.  See 
Appendix 1 for definition of adequate baseline tumor assessment.
If measurements for one or more target lesions are missing for an evaluation, the objective 
status for that evaluation is Indeterminate.
If non-target disease was not assessed, then a patient who qualifies for an objective status of 
CR based on target disease will be classified as PR.  Otherwise, missing non-target disease 
assessments generally do not affect response determination.  Such cases will be reviewed 
carefully by the clinical team.
Patients who do not have post-baseline tumor assessments and present with early death due 
to disease or early progression (ie, prior to first planned post-baseline tumor assessment) will 
be assigned a best response of PD.
Patients who come off trial early (prior to first planned post-baseline assessment) for reasons 
other than PD (early toxicity, withdrew consent, etc.) will be considered evaluable and 
Indeterminate for tumor response.
7.3. Missing Data in Safety Endpoints
There will be no imputation of missing data for any safety endpoints other than those 
explicitly specified.
The percentage of patients with an adverse event will be calculated using the number of 
patients in the safety analysis set as the denominator, regardless of whether there are missing 
data for AEs.
The denominator for summary tables for each laboratory test will be all patients in the safety 
analysis set with at least one evaluable cycle for that test.  Different laboratory tests may 
have different denominators, depending on the number of evaluable patients for each test.  
An evaluable cycle is any cycle with at least one assessment of that test. 
7.3.1. Missing QTc Data
For analyses using the QTc analysis set, no values will be imputed for missing data except 
for averaging of triplicate measurements.  If one or two of the triplicate measurements for an 
ECG endpoint are missing, the average of the remaining two measurements or the single 
measurement can be used in the analyses.  If all triplicate measurements are missing at a time 
point for an ECG endpoint, no values will be imputed for this time point.
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7.3.2. Missing Left Ventricular Ejection Fraction Data
For shift table summary or analysis of changes from baseline, the data for each patient must 
be derived from the same technique (echocardiogram [ECHO] or multi-gated radionuclide 
study [MUGA]).  Even though alternative techniques may be used for confirmation of 
results, all data for summaries must be derived from the technique used for baseline LVEF 
assessment. 
7.4. Missing Pharmacokinetic Data
7.4.1. Concentrations Below Limit of Quantification
In all data summaries and figures, concentrations below the limit of quantification (BLQ) 
will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ will be 
replaced with the value for the lower limit of quantification.)
7.4.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if one of the following cases is true:
•
A concentration has been reported as ND (ie, not done) or NS (ie, no sample);
•
A deviation in sampling time is more than 10% from the nominal time or a 
concentration has been flagged anomalous by the pharmacokineticist.
7.4.3. Pharmacokinetic Parameters
Whether actual or nominal PK sampling time will be used for the derivation of PK 
parameters will be determined by the results of interim PK analyses.
If a PK parameter cannot be derived from a patient’s concentration data, the parameter will 
be coded as NC (ie, not calculated).  (Note that NC values will not be generated beyond the 
day that a patient discontinues.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will not be presented for a particular arm with N less than 3.  For statistical analyses (ie, 
analysis of variance), PK parameters coded as NC will also be set to missing.
If an individual patient has a known biased estimate of a PK parameter (due, for example, to 
an unexpected event such as vomiting before the drug is completely absorbed in the body), 
this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
7.5. Missing Patient Reported Outcome Data
For the QLQ-C30 and QLQ-BR23 in cases where two answers are given to one item, the 
more severe answer will be counted.  For QLQ-C30 and QLQ-BR23, if at least half of the 
constituent items for the multi-item functional or symptom scale have been answered, then 
the score for that scale may be pro-rated based on the non-missing items.  Missing scale 
scores will not be imputed but considered missing for analysis purposes.
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7.6. Missing Biomarker Data
Patients with no biomarker results are not included in the biomarker analysis.  Patients with 
missing baseline biomarker assessment are not assessable for baseline description, for the 
examination of association with other endpoints, or for assessment of change from baseline.  
Patients missing follow-up biomarker assessments are not assessable for change from 
baseline.  No missing pharmacodynamic or tumor biopsy data will be imputed.
If an archival or fresh baseline tumor sample is missing, the patient cannot be assessed for 
genetic variations at baseline.
7.6.1. Handling of Duplicate Biomarker Data
Duplicate biomarker data for a visit are not expected.  However, if duplicate data for a visit 
are assayed by the vendor, the statistician will provide instructions to the programmer as to 
which, if any, record is to be used for analysis.  A flag will be included in the database 
indicating which record (if any) is selected for analysis. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
Standard statistical methods will be used for different types of variables:
•
Continuous: mean, standard deviation, median, and range;
•
Time-to-event: Kaplan-Meier estimate of survivor function, median time to event, 
Brookmeyer-Crowley confidence interval for median time to event, probability of 
event by a particular time point, log(−log) method with back transformation for 
confidence interval of estimated probability of event by a given time point;
•
Categorical: count and percentage of each category, confidence interval of the 
percentage based on normal approximation (or exact method if so specified);
•
Pearson’s correlation coefficient will be calculated for two continuous variables if 
their linear relationship is of interest;
•
For biomarker samples, summary statistics (eg, the mean and standard deviation, 
median, CV, and minimum/maximum levels of continuous, and frequency and 
percentages of categorical biomarker measures) will be determined at baseline and 
post-treatment for each arm by timepoint, as appropriate.  For each pair of specimens, 
the ratio-to-baseline or percent change of these same parameters will also be 
calculated.
In general, data will be summarized by arm, with the Arm B expansion summarized 
separately.
8.2. Statistical Analyses 
Refer to Section 5 for definitions of analysis sets.
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8.2.1. Analyses of Primary Endpoint
8.2.1.1. Dose escalation
Analysis set: Per protocol analysis set.
DLT is the primary endpoint.
The number of patients with DLTs will be summarized by dose level for each arm.  The 
number of patients with DLTs will also be summarized by dosing cohort for each arm.
A DLT listing will be provided by arm, which is a listing of the adverse events flagged as 
DLTs.
8.2.1.2. Arm B Expansion
Analysis set:  Response analysis set
Objective Response is the primary endpoint.
Objective response (CR + PR) will be summarized by count and percentage and a 95% exact 
confidence interval (CI) for the objective response rate will be provided by arm.
Best overall objective response will be summarized for each arm by count and percentage for 
each category as defined in Section 6.1.3.
8.2.2. Analysis of Safety Endpoints
Analysis set: Safety analysis set (unless indicated otherwise)
Summaries for safety endpoints will be by dose escalation arm, dose level, and Arm B
expansion arm.
8.2.2.1. Summaries of Adverse Events
The frequency of adverse events will be computed by counting each patient only once per 
MedDRA preferred term grouped by system organ class and according to the maximum NCI 
CTCAE grade attained by the patient over the specified period.  The percentage of patients 
with an event will be calculated using the number of patients in the safety analysis set as the 
denominator. 
Treatment-related AEs will be summarized in two ways (Arms A and B) or three ways (Arm 
C) based on the study drug(s) that the AE is attributed to: 
•
All treatment-related AEs;
•
PF-05212384-related AEs;
•
Dacomitinib-related AEs (Arm C only).
If a treatment-related AE is not attributed to any specific drug, it will be included in the 
summaries of PF-05212384-related AEs (all arms) and dacomitinib-related AEs (Arm C 
only). 
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The following summaries will be presented for all-causality and treatment-related 
treatment-emergent AEs separately.
An overall summary of treatment-emergent AEs will be presented with the following counts:
•
number of patients evaluable for AEs;
•
total number of AEs (counting each unique preferred term across all patients);
•
total number of SAEs (counting each unique preferred term across all patients);
•
number of patients with AEs;
•
number of patients with SAEs;
•
number of patients with Grade 3 or Grade 4 AEs;
•
number of patients with Grade 5 AEs;
•
number of patients who discontinued due to AEs (per the AE CRF page);
•
number of patients with dose decreases due to AEs (per the AE CRF page);
•
number of patients with dose delays due to AEs (per the AE CRF page).
The number and percentage of patients with treatment-emergent AEs will be summarized by 
MedDRA system organ class, preferred term, and maximum CTCAE grade by arm and dose 
level for all cycles combined.  The total for all grades will be included as the last column.  
The same summary will also be presented separately for AEs in lead-in period, AEs in 
Cycle 1 and AEs in Cycles beyond Cycle 1.
The number and percentage of patients with treatment-emergent AEs will be summarized by 
MedDRA preferred term and maximum CTCAE grade in descending order of frequency 
(based on total frequency for all grades) by arm and dose level for all cycles combined.  The 
total for all grades will be included as the last column.  The same summary will also be 
presented separately for AEs in lead-in period, AEs in Cycle 1 and AEs in Cycles beyond 
Cycle 1.
The number and percentage of patients with treatment-emergent SAEs will be summarized 
by MedDRA system organ class, preferred term, and maximum CTCAE grade by arm and 
dose level for all cycles combined.  The total for all grades will be included as the last 
column.  The same summary will also be presented separately for AEs in lead-in period, AEs 
in Cycle 1 and AEs in Cycles beyond Cycle 1.
The number and percentage of patients with treatment-emergent AEs of Grade 3-5 will be 
summarized by MedDRA preferred term and maximum CTCAE grade in descending order 
of frequency (based on total frequency for all grades) by arm and dose level for all cycles 
combined.  The total for all grades will be included as the last column.  The same summary 
will also be presented separately for AEs in lead-in period, AEs in Cycle 1 and AEs in Cycles 
beyond Cycle 1.
Additional tables may be provided by grouping AEs of different CTCAE grades.
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8.2.2.2. Analyses of Laboratory Tests
The percentage of patients experiencing laboratory test abnormalities will be calculated using 
the number of patients in the safety analysis set with at least one evaluable cycle for that 
laboratory test as the denominator. 
The number and percentage of patients experiencing laboratory test abnormalities will be 
summarized according to worst CTCAE grade by laboratory test for each arm and dose level.  
The total for all grades will be included as the last column.  Separate tables will be generated 
for hematology, coagulation, chemistry, and urinalysis laboratory tests.  The same summaries 
will also be presented separately for laboratory tests in lead-in period, those in Cycle 1 and 
those in Cycles beyond Cycle 1.
Shift tables will be presented for baseline grade to worst post-baseline grade by laboratory
test for selected CTCAE graded hematology, coagulation, chemistry, and urinalysis 
laboratory tests for each arm and dose level, provided that there are at least 7 patients with 
non-missing baseline values at a dose level of an arm.  The total for all grades will be 
included as the last row and the last column.  One table will be generated for each category 
of safety laboratory tests (hematology, coagulation, chemistry, and urinalysis).
For laboratory tests without CTCAE grade definitions, the number and percentage of patients 
with laboratory tests meeting the criteria of abnormalities will be summarized for each arm 
and dose level by laboratory test according to worst post-baseline results for normal baseline, 
abnormal baseline and without regard to baseline, as appropriate. 
Incidence and non-CTCAE abnormality criteria (for non CTC graded labs) of 
hematology labs, coagulation labs, chemistry labs, and urinalysis labs for all cycles (Normal, 
Abnormal Low, and Abnormal High).
8.2.2.3. Hy’s Law Listing
A listing will be provided for patients who potentially meet Hy’s law criteria. Dates and 
results for total bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), and 
alkaline phosphatase (ALP) will be presented according to arm and dose level for all patients.
8.2.2.4. Analyses of Electrocardiogram Endpoints
Analysis Set: QTc analysis set
At each time point, for each ECG endpoint, data for a patient will be averaged.  All summary 
statistics and data presentations will use these averaged data.  Any data obtained from ECGs 
repeated for safety reasons after a nominal time point will not be averaged with the values 
obtained at the preceding nominal time point.  Interval measurements from these repeated 
ECGs will be included in the outlier analysis as individual values obtained at unscheduled 
time points, if unplanned ECGs are done in triplicates or duplicates the values will be 
averaged. 
A summary of ECG endpoints (HR, RR, PR, QRS, QT, and QTcF) will be provided by arm 
and dose level for each time point (n, mean, standard deviation, median, min, and max).
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A shift table will be provided by arm and dose level for ECG abnormality on treatment vs 
baseline (yes, no, not done ) for any dose level for which there are at least 7 patients with 
non-missing values at baseline.  Unevaluable results will be grouped with “not done.”
The following summaries will be based on QTcF only. 
Change from baseline will be summarized for QTcF by arm and dose level: baseline and 
change from baseline at each time point (n, mean, standard deviation, median, min, and 
max).
For each patient, the maximum (worst) post-baseline value and the maximum increase from 
baseline will be calculated across all post-baseline time points.
Categorical analysis (outlier analysis) of the data will be conducted and summarized by arm 
and dose level with the following categories:
•
Number of subjects with maximum increase from baseline in QTcF (≤30, >30-60, and 
>60 ms);
•
Number of subjects with maximum post-baseline QTcF (<450, 450-480, >480-500, 
and >500 ms).
A shift table of QTcF from baseline to worst post-baseline value will be provided by arm and 
dose level with QTcF categories based on CTCAE grades (<450, 450-480, >480-500, and 
>500 ms).
Additional concentration-QTcF analyses may be performed.  Data may be pooled with other 
study results and/or explored further with PK/PD models.
Summaries of corrected QT intervals based on other methods may be presented as 
appropriate.  If corrected QT intervals are reported on the CRF (QTc), they will not be 
summarized, but will be included in the listing of ECG data. 
8.2.2.5. Left Ventricular Ejection Fraction (Arm C Only)
A shift table of LVEF from baseline to worst post-baseline value will be provided by dose 
level with LVEF categories of <45%, 45%-<50%, 50%-<55%, and ≥55%.  Worst 
post-baseline value will be calculated as the minimum LVEF across all post-baseline time 
points.  “Not reported” may be included as a category. 
Change from baseline will be summarized for LVEF by dose level: baseline and change from 
baseline at each time point (n, mean, standard deviation, median, min, and max).
8.2.2.6. Listings for Safety Endpoints
All safety endpoints including AEs, laboratory tests, ECOG performance status, ECG, LVEF, 
physical examinations, and vital signs will be listed.  Where appropriate, changes from 
baseline to each assessment will be included.  In the listing of AEs, TEAEs will be flagged.
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Selected subsets of AEs will also be listed separately.  These include Grade 3-5 AEs (all 
causality and treatment related), SAEs (all causality and treatment related), SAEs per the 
safety database, treatment related SAEs with onset after 28 days from the last dose of study 
treatment, discontinuations due to AEs (all causality and treatment related), temporary 
discontinuations and dose reductions due to AEs (all causality and treatment related), all AEs 
for patients off treatment “due to AE” on subject summary page at the end of treatment, all 
AEs for patients coded as “permanently discontinued” on AE page.
Physical exam for screening and changes from screening will be listed.
Selected subsets of laboratory tests may also be listed separately, including Grade 
3-5 laboratory tests, abnormal laboratory tests without CTCAE grades.  Laboratory tests 
abnormalities by test and subject.
A listing of deaths will be presented for patients who die while on treatment or within 
28 days of permanent discontinuation of treatment (patient id, treatment stop date, 
progression date, date of death, cause of death). In addition, a listing of deaths will be 
presented for all patients who die on study. 
8.2.3. Analyses of Study Conduct 
Analysis set: Full analysis set
Summaries will include the following:
•
Summary of patient accrual by center and arm;
•
Summary of patient evaluation by arm: Number and percent enrolled, treated, 
assessed for adverse events, assessed for laboratory tests, and assessed for efficacy;
•
Summary of discontinuation from study by arm.
Listings will include the following:
•
Listing of patients enrolled but not treated;
•
Listing of inclusion and exclusion criteria deviations;
•
Listing of patients excluded from each analysis set, including the reason for the 
exclusion.
8.2.4. Analyses of Baseline Characteristics
Analysis set: Safety analysis set
8.2.4.1. Demographic Characteristics and Primary Diagnosis Related Characteristics
Patient baseline characteristics at study entry, as listed in Section 6.3.1, will be summarized 
by arm (Arm A, B, and C of the dose escalation and Arm B expansion arms).
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Demographic summary will include descriptive statistics for age, race, weight, and height by 
sex (male, female, and total).  Age will be summarized by age group (number and 
percentage) and as a continuous variable (mean, SD, median, range). 
ECOG performance status at baseline will be summarized by arm with number and 
percentage for each status. 
Summary of disease history will include primary diagnosis (number and percentage), and 
time from diagnosis to enrollment (median and range).
Summary of prior treatment for cancer under study will include prior radiotherapy (yes/no), 
prior surgeries (yes/no), number of prior systemic therapies (number and percentage for 
0, 1, 2, etc.).
Summary (and listing) of historical molecular biology of disease data will include the marker
data from the primary diagnosis page.
Patient disease will be summarized with respect to current disease stage (if appropriate), 
organ sites of disease (if appropriate), number of sites of disease (based on baseline 
assessment CRF page), and measurable disease (yes/no) for each primary diagnosis by arm. 
Listings will be provided for baseline data from which the above summaries are generated.
8.2.4.2. Medical History 
Relevant medical history findings will be summarized as past or present by arm.  If both past 
and present history findings are present for a condition, a patient will be counted under
present history only.
A listing of medical history will be provided.
8.2.4.3. Prior Drugs Taken and Prior Non-Drug Treatment
The number of patients who took prior drug treatments will be summarized by arm for drug 
treatments which were taken before first day of treatment but within 28 days of first dose of 
study treatment.  All prior drug treatments within the window will be included, whether or 
not they continue during treatment. 
The number of patients who took prior non-drug treatments will be summarized by arm for 
non-drug treatments which were taken before first day of treatment but within 28 days of first 
dose of study treatment.  All prior non-drug treatments within the window will be included, 
whether or not they continue during treatment. 
Listings of prior drug and non-drug treatments will be provided.
8.2.5. Treatment Descriptions
Analysis set: Safety analysis set
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8.2.5.1. Treatment Administration
The number and percentage of patients on treatment and off treatment for each reason will be 
presented by arm and dose level.
Treatment administration will be summarized for each drug and for overall (either or both of 
the two drugs), as appropriate, by arm and dose level:
•
Number (%) of patients starting lead-in period, 1, 2, 3, 4, 5+ cycles for each drug and 
for overall;
•
Number of cycles started (median, minimum, maximum) for each drug and for 
overall;
•
Summary of duration of treatment (days) for each drug and for overall;
•
Summary of days dosed: only days with dosing are counted;
•
Summary of total dose prescribed (sum of all prescribed doses on dosing records) and 
total dose administered (sum of all actual administered doses on dosing records) by 
drug;
•
Number (%) of patients with at least one dose reduction for each drug and for overall; 
for each drug, further divided into 1 reduction and ≥2 dose reductions;
•
Number (%) of patients with at least one missed dose which may be further broken 
down into 2 or more categories;
•
Number (%) of patients with at least one delayed cycle;
•
Number (%) of patients with infusion rate change (broken down by due to Adverse 
Event and due to Other reason) – IV drugs only;
•
Number (%) of patients with infusion interruption (broken down by due to Adverse 
Event and due to Other reason) – IV drugs only;
•
Number (%) of patients with any dose change (broken down by due to Adverse Event 
and due to Other reason) – dacomitinib only.
A summary listing will be provided that will include all patient-level variables summarized 
above.
Treatment administration in terms of relative dose intensity will be summarized by cycle and 
overall for each arm and dose level as below:
•
Cumulative dose received and percent of planned dose (the initial prescribed dose for 
the study prior to any dose reduction) for each drug.
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•
Relative Dose (RD) Intensity by cycle:  [cumulative dose in the cycle]/[intended 
cumulative dose per cycle] x 100.  The intended cumulative dose is constant for all 
cycles being fixed at the start of treatment.
•
Overall RD: [overall cumulative dose]/[intended cumulative dose per cycle x number 
of cycles] x 100.  The intended cumulative dose is constant for all cycles being fixed 
at the start of treatment.
A cycle-level listing will be presented by arm and dose level, which will include cycle 
number (starting from lead-in, if applicable), cycle start date, study day, cycle length, delayed 
from previous cycle (y/n), total dose received for each drug, and percent of planned dose for 
each drug. 
Dosing records will be listed.
8.2.5.2. Concomitant Medications and Non-Drug Treatments 
Concomitant and non-drug treatments refer to all drug and non-drug treatments received 
while on active treatment, whether or not they are recorded as prior treatments. 
A summary of concomitant drug and non-drug treatments may be provided. 
8.2.6. Analyses of Pharmacokinetics
8.2.6.1. Pharmacokinetic Concentrations
Analysis set: PK concentration analysis set 
Plasma pharmacokinetic parameters including the maximum plasma concentration (Cmax), 
time to maximum plasma concentration (Tmax), and area under the plasma concentration 
versus time curve (AUClast, AUCτ) for PF-05212384, docetaxel, cisplatin and dacomitinib
will be estimated using non-compartmental analysis.  If data permit or if considered 
appropriate, area under the plasma concentration versus time curve to infinity (AUCinf), 
terminal elimination half-life (t½), plasma clearance (CL), steady-state volume of distribution
Vss, and the observed accumulation ratio (Rac) will also be estimated. 
For PF-05212384, docetaxel, cisplatin, and dacomitinib, concentrations will be summarized 
descriptively (n, mean, SD, CV, median, minimum, maximum, geometric mean and its 
associated CV) by dose, cycle, day and nominal time for each arm and each drug.  Individual 
patient and median profiles of the concentration-time data will be plotted by dose, cycle and 
day (single dose and steady-state) using nominal times for each arm and each drug.  Median 
profiles will be presented on both linear-linear and log-linear scales.
Trough concentrations will be plotted for each arm, each drug and each dose using a 
box-whisker plot by cycle and day within cycle in order to assess the attainment of 
steady-state.
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8.2.6.2. Pharmacokinetic Parameters 
Analysis set: PK parameter analysis set.
To assess the pharmacokinetics of PF-05212384, docetaxel, cisplatin, and dacomitinib, the 
PK parameters detailed in Section 6.3.3 will be listed and summarized for patients in the PK 
analysis set (as defined in Section 5.4.3).  Missing values will be handled as detailed in 
Section 7.4.  Each PK parameter will be summarized by arm and day and will include the set 
of summary statistics as specified in the table below:
Table 4.  Summary Statistics to Be Calculated for Pharmacokinetic Parameters
Parameter
Summary statistics
AUClast, AUCinf*, 
Cmax, CL* and Vss*
N, arithmetic mean, median, CV%, standard 
deviation, minimum, maximum, geometric 
mean, geometric CV%
t1/2*
N, arithmetic mean, median, CV%, standard 
deviation, minimum, maximum
Tmax
N, median, minimum, maximum
*=if data permit
8.2.7. Analyses of Additional Efficacy
8.2.7.1. Dose Escalation
Analysis set:  Response analysis set 
There are two subsets for the dose escalation:
1. All patients; and,
2. Patients with measureable disease only.
Best objective overall response (OR) and CBR will be summarized with count and 
percentage for each category by arm.  If data permit, OR and CBR summaries may be further 
broken down by tumor type (and dose level) within each arm.
Waterfall plots will be presented by arm for maximum percent change in tumor size (sum of 
diameters) from baseline, with selected characteristics such as tumor type, dose level and/or 
best overall response identified. 
8.2.7.2. Expansion
Analysis set:  Response analysis set 
CBR will be summarized with count and percentage by arm.
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Duration of response will be calculated for patients with an objective response (CR or PR).  
The median duration of response will be estimated using Kaplan-Meier method for each arm.  
A 95% CI for the median of each arm will be provided using the Brookmeyer-Crowley 
method. 
A patient listing for duration of response will be provided and it will include: patient 
identification, treatment arm, first objective response date and study day of objective 
response, date and study day of last objective response, date of progression, censoring date, 
duration of response, and censoring reason.
Waterfall plots will be presented by expansion arm for the best percent change in tumor size 
(sum of diameters) from baseline, the largest decrease or smallest increase.
PFS will be listed by arm.  If data permit, the median PFS and its 95% confidence interval
using the Brookmeyer-Crowley method will be presented.
Posterior probabilities using a non-informative Jeffrey’s prior and various true response rates
will be used to calculate the probability of not being inferior to the true response rate given 
the expansion data observed.
8.2.7.3. Listings of Efficacy Endpoints for All Patients
All patients will be included in the listings.  As appropriate, footnotes will be applied to 
indicate inclusion in the response analysis set.
A listing of target lesion measurements, sum of diameters at each assessment, change from 
baseline and nadir, and investigator assessments will be provided.
A listing of efficacy to include arm, tumor type, dose level, date of enrollment, measurable 
disease (y/n), first treatment (lead-in drug, dose, and date), Cycle 1 Day 1 treatment (drugs, 
doses, and day [relative to first dose of treatment]), day of last treatment, best overall 
response, day of first CR [at an evaluation], most recent day of CR [at an evaluation], first 
day of PR [at an evaluation], most recent day of PR [at an evaluation], day of progression, 
day of decision to discontinue treatment, reason off treatment, day of death or last contact (if 
available), and cause of death (if applicable).  Day is relative to first dose of treatment: day = 
date of event − date of first dose + 1.
A tumor assessment listing will be provided by arm, tumor type, dose level and patient for 
each cycle, which will include: tumor assessments (target lesions [excluding lymph node 
target lesions], non-target lesions, lymph node target lesions, and new lesions), and the 
investigator overall objective tumor assessment.
8.2.8. Patient Reported Outcomes
Analysis of the PRO endpoints will be based on the PRO analysis set.  The PRO analysis 
endpoints will be based on the instruments QLQ-C30 and QLQ-BR 23.  For each treatment 
group and at each time point, the number and percentage of patients who completed these 
instruments will be summarized, as will the reasons for non-completion of these measures.  
An instrument is considered completed if at least one item was answered by the patient. 
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EORTC QLQ-C30
This questionnaire contains 30 questions organized into 5 multi-item functional scales, 
3 multi-item symptom scales, a global quality of life scale, and 6 single item symptom scales.  
For each of the 15 scales, the results will be summarized using means (and standard 
deviation), 95% confidence interval, and medians (and range) for each arm at each time 
point.  This will be done based on the observed values as well as changes from baseline 
within the arm.
For each of the 15 scales, a graphical display of means over time as well as mean changes 
from baseline over time will also be provided.
EORTC QLQ-BR23
This questionnaire contains 23 questions organized into 4 functional scales and 4 symptom 
scales.  As with C30, the analysis of the BR23 scales will consist of descriptive statistics on 
means and changes from baseline.  Also, as with C30, graphical displays of means and 
changes from baseline over time will also be provided for each BR23 scale. 
Patients will be classified as “improved,” “stable,” or “deteriorated” according to a 10-point 
or greater change in score as this change is perceived by patients as being clinically 
significant on the EORTC QLQ C30.5,8 Improved will be defined as at least a 10-point 
change in a “good” direction, deteriorated as at least a 10-point change in a “bad” direction, 
and stable if the patient neither improved nor deteriorated.
In addition to the change from baseline in scores, the proportion of patients whose scores 
improved, deteriorated, or remained stable over treatment will be evaluated with the PRO 
evaluable population.
In addition to the above analyses, an examination of the time to deterioration (TTD) will be 
carried out using survival analysis methods including Kaplan Meier plots.  Deterioration will 
be defined as a decrease of a pre-specified number of points based on MID (minimal 
important difference).  This analysis will be carried out for the variable Global Health 
Status/QoL and an MID of 10 points will be used. 
8.2.9. Analysis of Biomarkers
Analyses of biomarkers are secondary for the dose escalation phase 
 
8.2.9.1. Analyses of Molecular Profiling Biomarkers
Analysis Set: Molecular profiling tumor analysis set.
8.2.9.1.1. Molecular Biomarkers
Dose escalation and expansion will be summarized separately.
A list of mutations and alterations to be summarized for the baseline tumor biopsies will be 
provided prior to database release (these may include KRAS, BRAF, PTEN).
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Summary Analyses will include:
•
Mutation and other biomarker data will be summarized by arm, tumor type, and/or 
dose level, if data permit.
•
Associations of mutations and other biomarkers versus best overall response will be 
assessed (ie, count and % in each response category for each mutation or other 
biomarker) by arm, tumor type, and/or dose level, if data permit.
•
A summary of demographics will be produced by arm if the sample size of the 
molecular profiling tumor analysis set is less than 80% of the total sample size for 
any arm:
•
Data will be presented to show the copy number alteration or mutation by patient 
along with change from baseline in tumor size in a waterfall plot.
•
A listing of biomarkers by arm will be produced: all biomarker data collected will be 
listed.  Patients included for summaries with best overall tumor response will be 
flagged.
For assessment of associations with best overall response, only those patients who are part of 
the molecular profiling tumor analysis set and the response analysis set will be included.  For 
other summaries, all patients in the molecular profiling tumor analysis set will be included.
8.2.9.2. Analyses of Expression Biomarkers 
Analysis set:  Expression tumor analysis set 
For paired fresh tumor biopsies, time points consist of Screening (baseline), and C2D8
 
.  A list of proteins and corresponding antibody epitopes to be 
summarized will be provided prior to database release (these may include pAkt, pErk). 
Analyses will include:
•
Baseline, C2D8
and ratio of C2D8
 
 to baseline will be summarized.  Paired C2D8
and baseline data will be analyzed using Wilcoxon signed-rank test by arm, tumor 
type, and/or dose level if the number of pairs is at least 10;
•
A summary of ratio of C2D8
to baseline, as well as 
baseline and C2D8
stand-alone biomarker value, versus 
best overall response will be provided by arm and dose level, if data permit;
•
A summary of demographic and baseline characteristics will be produced if the 
sample size of the expression tumor analysis set is less than 80% of the total sample 
size for any arm.  The characteristics to be summarized will be selected before 
database release:
&&,
&&,
&&,
&&,
&&,
&&,
&&,
&
&,
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•
Plots of percent inhibition of phosphor-protein will be provided.  The plot will 
include a bar for each protein with the patient value, the median value, and the 
minimum and maximum values of the population.  Proteins may include pAkt, 
pErk, as well as others.
•
A listing of protein data by arm will be produced: all biomarker data collected will 
include a flag indicating inclusion in summaries with overall best tumor response.
For the summaries of ratio of C2D8
 to baseline versus best overall 
response, only those patients who are part of the expression tumor analysis set and the 
response analysis set will be included.  For other summaries, all patients in the expression 
tumor analysis set will be included.
8.2.9.3. Analyses of Serum Pharmacodynamic (PD) Biomarkers
Analysis set: Serum PD analysis set
Dose escalation and expansion will be summarized separately.
PD biomarkers (including serum glucose, insulin, and HbA1c) are measured at screening 
(baseline) and multiple time points post baseline (including C1D8, C1D15, C2D1, C2D15, 
and EoT).  Baseline is defined as the last measurement prior to dosing, which is the 
measurement at screening or the C1D1 pre-dose measurement if collected:
•
Baseline, CxDy, and ratio of CxDy to baseline, as appropriate, will be summarized.  
Paired data (CxDy and baseline data) will be analyzed using Wilcoxon signed-rank 
test, by arm, tumor type, and/or dose level, for time points at which the number of 
pairs is at least 10;
•
A summary of baseline and ratio of CxDy to baseline versus best overall response 
will be provided, by arm and by dose level, if data permit;
•
Spaghetti plots and box plots for each biomarker will be provided, by arm and dose;
•
A listing of PD biomarkers by arm will be produced.
For the summary of ratio of CxDy to baseline versus best overall response, only those 
patients who are part of the serum PD analysis set and the response analysis set will be 
included.  For other summaries, all patients in the serum PD analysis set will be included.
 
 
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9. REFERENCES 
1.
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for 
dose-finding trials. Clin. Trials. 2010;7(6):653-663.
2.
Liu S, Yuan Y.  Optimal interval designs for Phase 1 clinical trials.  Statistics in 
Medicine. 2012.  revised. 
3.
Huang X, Biswas S, Oki Y, Issa JP, Berry DA. A parallel Phase I/II clinical trial design 
for combination therapies. Biometrics. 2007;63(2):429-436.
4.
Oron AP, Azriel D, Hoff PD.  Dose-finding designs: the role of convergence properties.  
International Journal of Biostatistics. 2011; 7(1):1–17.
5.
Osoba D et al, Interpreting the significance of changes in health related quality of life 
scores. J. Cin Oncology. 1998. 16:139-144.  
6.
Aaronson NK et al. The European Organization for Research and Treatment of Cancer 
QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology.  J Natl Cancer Inst  85:365-76, 1993
7.
Fayers P, Bottomley A. Quality of Life Research within the EORTC – The EORTC 
QLQ-C30, on behalf of the EORTC Quality of Life Group. European Journal of Cancer. 
38 (Suppl4):125-133, 2002. 
8.
Fayers P et al. EORTC QLQ-C30 Scoring Manual. 2001. EORTC, Brussels.
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10. APPENDICES
Appendix 1. DATA DERIVATION DETAILS
Appendix 1.1. Definition and Use of Visit Windows in Reporting
Enrollment
Assignment of enrollment number, treatment arm and 
dose level. 
Treatment start
First dose of treatment, typically the PK lead-in dose.  
Planned Cycle Length
Planned cycle length is 21 days.
Day 1 of a cycle (cycle start date)
Day 1 of a cycle per Schedule of Activities. 
For Arm A, Day 1 of a cycle is defined as the day on 
which the patient receives docetaxel. 
For Arm B, Day 1 of a cycle is defined as the day on 
which the patient receives cisplatin. 
For Arm C, Cycle 1 Day 1 is the day on which the 
patient receives dacomitinib after the lead-in dose, 
and Day 1 for Cycles 2 and beyond is defined as the 
day on which the patient receives PF-05212384.
For all arms, if only one drug remains being 
administered, Day 1 of a cycle x (x≥2) is defined as 
the day on which the patient receives this drug.
Cycle length (all but final cycle)
Cycle length is length from Day 1 of a cycle to the 
day prior to Day 1 of the next cycle.
Final cycle
For patients on treatment, from Day 1 of most recent 
cycle start to protocol specified cycle length.
For patients withdrawn from treatment, from Day 
1 of most recent cycle to 28 days post final dose.
DLT evaluation period
From the PK lead-in dose through Cycle 2 Day 1.
Baseline safety laboratory values
Baseline safety laboratory values are collected within 
14 days prior to the first dose of study drug and are 
from a time point closest to, but prior to, start of 
study drug. 
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Baseline ECGs
Baseline ECGs are within 14 days of first dose of 
study drug and are from a time point closest to, but 
prior to, start of study drug.
Baseline LVEF
Baseline LVEF values are within 28 days of first dose 
of study drug and are from a time point closest to, but 
prior to, start of study drug.
Baseline ECOG performance score
Baseline ECOG performance scores are assessed
within 14 days of first dose of study drug and are 
from a time point closest to, but prior to, start of 
study drug.
Adequate baseline tumor 
assessment
All required scans must be done within 28 days prior 
to first dose of study drug and all disease sites must 
be documented appropriately.  The specific 
requirements include: 
•
all known disease sites are assessed at baseline 
and documented on baseline assessment CRF; 
•
all tumor assessments at baseline are within 
28 days of first dose of study drug (baseline 
assessment CRF and tumor lesions CRFs); 
•
for target lesions other than malignant lymph 
nodes, the longest diameter must be ≥ 10 mm by 
CT scan or caliper, and ≥ 20 mm by chest X-ray; 
•
for malignant lymph nodes as target lesions, the 
short axis must be ≥ 15 mm by CT; 
•
target lesions are truly measurable 
(non-measurable lesions are listed in RECIST 
v1.1 Guidelines, as adapted in Appendix 2 of the 
protocol); 
•
method of assessment is reliable, eg, ultrasound is 
not useful in assessment of lesion size; and 
•
description is provided for all non-target lesions.
Cycle k +1 delay
Time from Cycle k Day1 to Cycle k+1 Day 1 is 
greater than the planned cycle length.
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Appendix 2. STATISTICAL METHODOLOGY DETAILS 
Appendix 2.1. Interval Design for Arms A and B
An interval design for MTD finding assigns a dose to a new cohort of patients based on the 
estimated DLT rate of the current dose compared to a pre-specified interval of DLT rate.4 In 
this appendix, a general interval design for a single-agent MTD finding trial (or arm) is 
described, followed by a description of specific implementation in Arms A and B.
A General Interval Design
Suppose that J doses of an agent are investigated in a trial (or arm).  Let 
jp be the 
probability of DLT for the j-th dose, j = 1, …, J. Assume monotonic dose-DLT relationship,
J
p
p
p
<
<
<
...
2
1
.  The objective of the trial is to find the dose, s, at which the probability of 
DLT is closest to the target, 
T
p , among all doses, 
|
|
argmin1
T
j
J
j
p
p
s
−
=
≤
≤
.
The first cohort of patients can be assigned arbitrarily to a dose.  However, to protect patient 
safety, the dose for the first cohort of patients should be selected based on the following rule.
1. The dose assigned to the first cohort of patients is deemed highly likely to be 
tolerable, eg, dose 1 or dose 2.
Suppose that dose j is the current dose with which patients are treated and 
)1
(
≥
j
j n
n
patients have been treated cumulatively with this dose. Of the 
jn patients, 
)
(
j
j
j
n
x
x
≤
patients have experienced DLTs. Let 
j
j
j
n
x
p
/
ˆ =
. Let
0
)
(
>
Δ
j
L n
and 
0
)
(
>
Δ
j
U n
be 
functions of 
jn such that (
))
(
),
(
j
U
T
j
L
T
n
p
n
p
Δ
+
Δ
−
defines an interval of DLT rate.  
Starting from the second cohort, the dose assignment rule is as follows:
2. if
)
(
ˆ
)
(
j
U
T
j
j
L
T
n
p
p
n
p
Δ
+
<
<
Δ
−
, the next cohort of patients will be 
assigned to dose j again;
3. if 
)
(
ˆ
j
L
T
j
n
p
p
Δ
−
≤
, the next cohort of patients will be assigned to dose 
j+1 (unless
J
j =
in which case dose J will be assigned again);
4. if 
)
(
ˆ
j
U
T
j
n
p
p
Δ
+
≥
, the next cohort of patients will be assigned to dose
j−1 (unless 
1
=
j
in which case dose 1 will be assigned again).
Note that in other interval designs, 
L
Δ
and 
U
Δ
may depend on additional parameters or may 
be constants.  For convenience, (2) is also called "stay" or “S,” (3) is also called "escalate" or 
“E,” and (4) is also called "de-escalate" or “D.”
In practice, due to concern of exposing too many patients to a toxic dose, it is desirable to 
stop assigning patients to a dose for which cumulative data suggest to be most likely too 
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toxic.  A Bayesian dose elimination rule can be added to the dose assignment rule for this 
purpose:1,2
5. If
3
≥
jn
and 
0.95
data)
|
Pr(
>
>
T
j
p
p
, then doses j and higher will be
eliminated from further testing in the trial, and the trial will be terminated if 
the first dose is eliminated.
Here
data)
|
Pr(
T
j
p
p >
is evaluated based on a beta-binomial model. Assuming that the 
number of patients experiencing DLTs, 
j
X , follows a binomial distribution (with size and 
probability parameters 
jn and 
jp ) and 
jp has a prior distribution of beta(1,1), then the 
posterior distribution of 
jp is beta(
j
j
j
x
n
x
−
+
+
1
,
1
).
Typically, a trial using an interval design ends when it reaches the planned sample size or 
when the lowest dose is eliminated due to the dose elimination rule. Additional 
considerations may be added.
At the end of the trial, isotonic estimates of DLT rates are calculated and used as the basis for
the selection of estimated MTD:1,2 select as the estimated MTD the dose for which the 
difference between the isotonic estimate of DLT rate and 
T
p is the smallest among all tested 
doses, ie,
|
~
|
argmin
~
1
T
j
J
j
p
p
s
−
=
≤
≤
, where dose s~ is the estimated MTD, and
jp~ is an 
isotonic estimate of 
jp .  If two or more doses share the same isotonic estimate of DLT rate, 
then the estimated MTD will be the highest dose in the case that the isotonic estimate is 
lower than 
T
p , and the lowest dose in the case that the isotonic estimate is greater than 
T
p .
Implementation in Arms A and B
The doses available for each are arm are listed in Table 1.The target DLT rate is 
25
.0
=
T
p
.  
The first cohort of patients will be treated with dose levels A1 and B1, respectively.  As of 
July 2014, dose levels A1 and A2 and B1, B2, and B3 have been tested and found to be 
tolerated without DLTs.  The starting dose level for the purposes of the simulations is A1 and 
B1 with 8 dose levels expected to be administered.
For 
4
2
≤
≤
jn
, dose assignment will be based on the mTPI method with 
25
.0
=
T
p
and 
equivalence interval of [0.20, 0.32], which can be viewed as an interval design with 
)
(
j
L n
Δ
and 
)
(
j
U n
Δ
in the table below; for 
5
≥
jn
, 
051
.0
)
(
=
Δ
j
L n
and 
071
.0
)
(
=
Δ
j
U n
are selected 
so that an observed DLT rate in [0.20, 0.32] will result in a dose assignment of “Stay” for 
25
5
≤
≤
jn
.
jn
2
3
4
≥5
)
(
j
L n
Δ
0.10
0.10
0.10
0.051
)
(
j
U n
Δ
0.26
0.15
0.10
0.071
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For ease of use, rules (2)-(5) specific to Arms A and B are presented in a matrix of E/S/D/DU 
for all possibilities of 
jx for 
15
2
≤
≤
jn
, where E=Escalation, S=Stay, D=De-escalation and 
DU=Elimination due to unacceptable toxicity.  The format of this matrix follows Ji et al 
[2010].1
For Arms A and B, the MTD estimate will be selected using the approach of the general 
interval design with the additional requirement that the isotonic estimate of DLT rate for the 
estimated MTD must be less than or equal to 32%.
Modified Toxicity Probability Interval (mTPI) Method
As the mTPI method is used for 
4
2
≤
≤
jn
, a brief description of the method based on its 
own framework1 is provided here.
The mTPI method is a Bayesian method with only one assumption about the dose-toxicity 
relationship, which is, toxicity increases as dose increases.  The most important parameter of 
the mTPI design is the target DLT rate at the MTD, which is 0.25 for this study.  An interval 
for DLT rate, called equivalence interval, is also required for the mTPI method.  Any DLT 
rate in the equivalence interval is considered sufficiently close to the target DLT rate for the 
purpose of MTD estimation.  In this study, the equivalence interval is [0.20, 0.32].  For each 
dose level, the uniform prior is assumed for the DLT rate. 
Dose assignment recommendations are based on the posterior distribution of the DLT rate.  
Specifically, the DLT rate on (0, 1) is divided into three intervals: the equivalence interval, 
the interval below it, and the interval above it.  Unit probability mass (UPM) is calculated for 
each of these intervals based on the posterior distribution of the DLT rate.  The mTPI method 
recommends a higher dose level to the next cohort of patients if the interval below the 
equivalence interval has the highest UPM at the current dose level; and it recommends a 
lower dose level to the next cohort of patients if the interval above the equivalence interval 
has the highest UPM at the current dose level.  To protect patients from highly toxic dose 
levels, a dose level is considered unacceptably toxic and eliminated from further testing, if 
the posterior probability is 95% or higher that its DLT rate is above the target DLT rate.
The MTD estimation at the end of the trial for the general interval design is the same as the 
approach of the mTPI method. 
Simulations for Interval Design Implemented for Arms A and B
The interval design as implemented for Arms A and B were examined via simulations.  For 
each simulation, a sample size of 40 is used with a cohort size of 3 patients.  Five scenarios 
were simulated with 10,000 simulations each.  The simulation results are summarized in the 
table that follows.  The frequency of the true MTD being selected if all 40 patients are 
enrolled by the interval design ranges from 58% to 89%, which are deemed satisfactory.  The 
frequency of the true MTD being selected if 30 patients are enrolled is 53% to 81% (results 
not shown).
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Dose Level
1#
2
3
4
5
6
7
8
Scenario 1
   True DLT rate
0.02
0.05
0.25
0.50
0.6
0.7
0.8
0.9
   Mean number of 
patients treated
3.3528
9.4656
20.3553
8.1030
0.6816
0.0393
0.0024
0.0
   Mean number of 
patients with DLTs
0.0673
0.4718
5.0665
4.0585
0.4057
0.0273
0.002
0.0
   Frequency 
selected as MTD
0.0000
0.0509
0.8904
0.0576
0.0011
0.000
0.00
0.00
Scenario 2
   True DLT rate
0.02
0.05
0.10
0.25
0.5
0.6
0.7
0.8
   Mean number of 
patients treated
3.3366
4.3722
10.2312
16.6578
6.7098
0.6471
0.0447
0.00
   Mean number of 
patients with DLTs
0.0668
0.2233
1.0247
4.2012
3.3318
0.3918
0.0310
0.00
   Frequency 
selected as MTD
0.00
0.0021
0.1615
0.7629
0.0709
0.0026
0.00
0.00
Scenario 3
   True DLT rate
0.02
0.05
0.10
0.10
0.25
0.5
0.6
0.7
   Mean number of 
patients treated
3.3369
4.2357
5.4972
8.9586
13.7136
5.6715
0.5508
0.0357
   Mean number of 
patients with DLTs
0.0693
0.2103
0.5526
0.8970
3.4233
2.8307
0.3328
0.252
   Frequency 
selected as MTD
0.0000
0.0008
0.0276
0.1768
0.7164
0.0754
0.0028
0.0002
Scenario 4
   True DLT rate
0.01
0.02
0.05
0.05
0.05
0.10
0.25
.50
   Mean number of 
patients treated
3.120
3.3474
3.7638
3.7803
4.2186
7.9455
10.9323
4.8906
   Mean number of 
patients with DLTs
0.0307
0.0714
0.1851
0.1882
0.2180
0.7812
2.7434
2.4528
   Frequency 
selected as MTD
0.0000
0.0000
0.0014
0.0031
0.0109
0.2053
0.7106
0.0683
Scenario 5
   True DLT rate
0.0000
0.0000
0.000
0.0100
0.0200
0.0500
0.1500
0.2500
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Protocol B2151002 Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 51
   Mean number of 
patients treated
3
3
3.0039
3.1164
3.3408
5.0304
8.9601
12.3021
   Mean number of 
patients with DLTs
0.0000
0.0000
0.0000
0.0000
0.00686
0.2563
1.3543
3.0638
   Frequency 
selected as MTD
0.0000
0.000
0.000
0.000
0.0002
0.0181
0.3652
0.5810
# starting dose.
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Protocol B2151002 Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 52
Appendix 2.2. Definition of Progression-Free Survival (Expansion only)
PFS (Primary Definition – Specific to This Study): Requires Objective Progression 
Documentation
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline assessment 
Start Date
Censored
No on-study assessments
Start Date
Censored
Alive, not started new anti-
cancer treatment and no 
progression
Date of last objective tumor 
assessment documenting no 
progression
Censored
Progression documented on or 
between scheduled tumor 
assessments 
Date of first objective tumor 
assessment documenting 
objective progression
Progressed (Event)
New anticancer treatment after 
discontinuation of treatment 
without progression
Date of last objective tumor 
assessment documenting no 
progression prior to new 
anticancer treatment
Censored
Death prior to 13 weeks since 
start date
Date of death
Death (Event)            
Death without objective 
progression 
Date of death
Death (Event)
                  
Death or progression after 2 or 
more missed tumor assessments 
(>13 weeks since last tumor 
assessment within the first 
12 cycles or > 19 weeks from 
cycle 13 on)
Date of last objective tumor 
assessment documenting no 
progression prior to the event
Censored
1: For date of censorship, if a tumor assessment takes place over a number of days (eg, superficial lesions one 
day, scans another), the last date is used as the assessment date.
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